Introduction

Cancer is known to be a leading cause of death worldwide, accounting for 10 million deaths in 2020, or one in six deaths. The most common cancers are breast, lung, colorectal, and prostate. Among them, lung, colorectal, and liver remain the most common causes of cancer deaths accounting for 3.5 million deaths, which is about one-third of total cancer deaths in 2020 (World Health Organization 2022). Premature deaths, lost productivity costs, illness and therapy expenses, and the long-term impact on quality of life all contribute to cancer being a major public health threat. (National Cancer Institute). Many cancers can be cured if detected early and treated effectively. There are different conventional treatment modalities available to treat cancer. Chemotherapy is considered the most effective and extensively used approach. It targets the tumor cells and mainly produces reactive oxygen species, which destroy tumor cells through genotoxicity. However, it harms normal cells and leads to diverse dose-dependent side consequences such as fatigue, nausea, hair loss, vomiting, or even death in extreme cases (DeVita and Chu 2008; Aslam et al. 2014; Abbas and Rehman 2018).

Natural plants are excellent sources of bioactive components, such as flavonoids, tannins, alkaloids, and terpenoids that have been confirmed to possess anti-cancer activities. Moreover, these components, when used as nanoparticles, can exhibit more specific advantages, such as biocompatibility, reduced toxicity, excellent stability, enhanced permeability, and precise targeting (Abdalla et al. 2022).

Medicinal plants have been utilized as remedies since ancient times in Egypt. The ancient Egyptians possessed knowledge about numerous medicinal herbs and their effectiveness in treating various illnesses. Today, some of these same plants continue to be utilized (Metwaly et al. 2021).

This review aims to explore the existing research on plants grown in Egypt with anticancer activity. These plants are thoroughly discussed in terms of the part(s) used, active constituents, mechanism of action, and their effects on different cell lines. Clinical trials and the efficacy of nanoparticles derived from these plants have also been reviewed.

Methods

An independent literature survey was performed using PubMed and Scopus. The search process was limited to English-language peer-reviewed articles published since 1994 till February 2023. Scopus was searched for the following keywords: Medicinal plants, Egypt, and cancer. The same keywords were searched on PubMed using the "Grid Term" option. The data collection period was from November 15, 2022, to November 29, 2022. The inclusion criteria for this systematic review were original research articles peer-reviewed in English. The authors first screened the studies by title, followed by a second step of screening by abstract. The full-text screening step excluded reviews, duplicate articles, abstract-only and irrelevant studies. A total of 286 studies were included. Figure 1 shows the PRISMA flowchart, and the number of items screened.

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PRISMA Flow Diagram, showing the number of screened and selected articles

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Results

In this review, 97 medical plants were investigated including details on the parts used, active compounds, and their effects on different cell lines. Most of these plants contained flavonoids and phenols as their active ingredients. These extracts were most used against breast and colon cancer cell lines. Several in vivo and in vitro studies showed the cytotoxic effect of these Egyptian plants, shown in Table 1. Nanoparticles, of various sizes, of the extract of 28 plants were used against different cancer cell lines. As a more advanced approach, clinical trials were conducted to assess the effectiveness of 14 plant extracts. Promising results were observed for some extracts, as indicated in Table 2.

Table 1 Anticancer effects of various Egyptian medicinal plants
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Table 2 Clinical trials showing anticancer activities of medicinal plants cultivated in Egypt
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Discussion

From the findings, 97 Medicinal plants in Egypt have anticancer potential. These plants contain different active constituents that show different mechanisms of action and target several cancer types.

Breast cancer

Breast cancer is a malignant tumor that arises in the lining epithelium of the ducts or lobules in the glandular tissue of the breast. It is the most prevalent cancer among women and the most common cancer overall. In 2020, there were 2.3 million women diagnosed with breast cancer and 685,000 deaths globally (Ferley et al. 2014; World Health Organization 2021). About 1 in 8 women are diagnosed with breast cancer during their lifetime (National Cancer Institute). Breast cancer is not a transmissible or infectious disease. Unlike some cancers that have infection-related causes, there are no known viral or bacterial infections linked to the development of breast cancer. Approximately half of breast cancers develop in women who have no identifiable breast cancer risk factor other than gender (female) and age (over 40 years). Breast cancer most commonly presents as a painless lump or thickening in the breast. Seeking medical attention at the first sign of a potential symptom allows for more successful treatment. Breast cancer treatment can be highly effective, achieving survival probabilities of 90% or higher, particularly when the disease is identified early. Scientific and research interest is drawing attention towards naturally derived compounds as they are considered less toxic, compared with current treatments (Greenwell and Rahman 2015). Egypt is well-known for its long-standing history of herbal medicine. Medicinal plants have been used as a source of remedies since ancient times in Egypt and the ancient Egyptians were familiar with many medicinal herbs and recognized their effectiveness in the treatment of various diseases (Azim 2011). The plant kingdom produces secondary metabolites that are investigated for anticancer activity and the development of new drugs (Greenwell and Rahman 2015). Regarding breast cancer, this review illustrates that 55 plants showed anti-cancer activities against 10 different breast cancer cell lines including MCF-7, BT-474, SKBR-3, MDA-MB231, MDA-MB-468, T-47D, EMT-6, hTERT-HME1, Hela and HCC-1937. It was also used against a murine mammary 4T1carcinoma and Ehrlich’s ascites carcinoma in mice.

Many clinical trials were conducted to ascertain the cytotoxicity of Egyptian medicinal plant extracts or their adjuvant role with chemotherapeutic agents. Oral GSP (Camellia sinensis or Black tea) increased the bioavailability of EGCG, which was detectable in breast tumor tissue and was associated with anti-proliferative effects on breast cancer tissue (Lazzeroni et al. 2017). Ginger (Zingiber officinale) supplementation alone or in combination with training, also played an important role in the pathogenesis of oxidative stress in obese women diagnosed with breast cancer (Karimi and Roshan 2013). Supplementation with Boswellia, betaine,and myo-inositol reduced fibroadenoma dimension in young women with no relevant side effects recorded (Pasta et al. 2016). N. sativa extract significantly decreased the severity of ARD and delayed the onset of moist desquamation in breast cancer patients (Rafati et al. 2019). Oral ART was used in a phase I clinical trial as an add-on to the guideline-based oncological therapy in patients with metastatic breast cancer (von Hagens et al. 2017).

Many strategies have been developed for targeting natural anti-cancer compounds in cancerous breast cells including gold nanoparticles (AuNPs) of Atriplex (Hosny et al. 2021), ursolic acid from Rosmarinus officinalis extract using nano-drug delivery systems (Shao et al. 2020), Nickel-ferrite (NiFe2O4) and iron nanparticles of Rosmarinus officinalis (Farshchi et al. 2018; Alijani et al. 2020) copper oxide (CuO), zinc oxide (ZnO) nanoparticles (NPs) of extracts from the leaves of Dovyalis caffra (Adeyemi et al. 2022), extract from Origanum majorana and silicon nanoparticles (Jssim and Abdul-Halim 2020), silver nanoparticles (Ag-NPs) of Beta vulgaris extract (Venugopal et al. 2017), C. sinensis tea fraction nanoparticles (Kusmiyati et al. 2022), phytofabricated gold nanoparticles of Plectranthus amboinicus (Hasibuan and Sumaiyah 2019), silver and selenium nanoparticles of trigonella foenum-graecum (Ramamurthy et al. 2013; Pansare et al. 2016; Abdellatif et al. 2022), palladium-silver, palladium–platinum, gold and silver nanoparticles of Nigella sativa (Gulbagça et al. 2022), Gold nanoparticles (GNPs) of Lawsonia inermis (Firdhouse and Lalitha 2017; Alhomaidi et al. 2022), silver nanoparticles of Phlomis aurea Decne (Abdelhady et al. 2016), silver, Se-CuO and cerium oxide nanoparticles of Cassia angustifolia (Bharathi and Bhuvaneshwari 2019; Antony et al. 2022; Pavan Kumar et al. 2022), zinc oxide nanoparticles of Catharanthus roseus (Bangroo et al. 2022) and gold nanoparticles of Nerium oleander (Barai et al. 2018), Most of these nanoparticles were used against MCF human breast cancer cell line.

Leukemia

Leukemia is a malignant condition involving the excess production of immature or abnormal leukocytes, which eventually suppress the production of normal blood cells and results in symptoms related to cytopenia (Emadi and Law 2022). The incidence of leukemia is 14.1 per 100,000 men and women per year. The death rate is 6.0 per 100,000 men and women per year. Fortunately, the 5-year relative survival of leukemia is 65.7% (National Cancer Institute). Regarding leukemia, this study illustrates 14 Egyptian medicinal plants showed anti-cancer activities through various mechanisms against 8 different human leukemia cancer cell lines including CCRF-CEM, HL-60, MOLT-4, K-562, U-937, THP-1, 1301, and Jurkat. It was also used against a mice macrophage cell line which is RAW 264.7.

Patients with early-stage, untreated chronic lymphocytic leukemia (CLL) are at high risk for acute respiratory illness (ARI), according to a double-blind, placebo-controlled, randomized trial of 293 patients. This clinical trial evaluated the safety and efficacy of Panax quinquefolius extract in reducing ARI. It was observed that lower rates of moderate-to-severe ARI and significantly lower rates of sore throat existed, implying that the increased rate of seroconversion (fourfold increases in antibody titer) towards 9 common viral pathogens. However, it did not decrease the number of ARI days or antibiotic use (High et al. 2012). Epigallocatechin-gallate (EGCG), an active constituent of green tea, has been shown in clinical research to have antitumor effects on hematologic malignancies such as chronic lymphocytic leukemia (CLL). It is interesting to note that during the green tea consumption phase, serum levels of IL-10 and TGF-beta decreased in both patients and controls. According to these findings, green tea may be able to control circulating T cells in CLL patients who are in the early stages of the disease. As a result, lymphocytosis and the prevention of disease progression may be under control (D’Arena et al. 2013).

Laryngeal cancer

Laryngeal cancers represent one-third of head and neck cancers and are often diagnosed in patients with a significant smoking history (Koroulakis and Agarwal 2022). The rate of new cases of laryngeal cancer is 2.8 per 100,000 men and women per year and the death rate is 0.9 per 100,000 men and women per year (National Cancer Institute). Regarding Laryngeal cancer, this review illustrates 6 Egyptian medicinal plants that showed anti-cancer activities through various mechanisms against Hep-2 which is a human Laryngeal cancer cell line.

Glioblastoma

Glioblastoma (GBM) is the most aggressive primary malignant brain tumor. It has an incidence rate of 3.19 per 100,000 persons in the United States and a median age of 64 years. Survival from GBM is poor; only a few patients survive 2.5 years and less than 5% of patients survive 5 years following diagnosis (Tamimi and Juweid 2017). This review illustrates 6 Egyptian medicinal plants that showed anti-cancer activities through various mechanisms against 8 different Human glioblastoma cancer cell lines including A-172, U-87 MG, SHG-44, GBM-8901, GBM-8401, SJ-G2, SMA and U-373. It was also used against rat glioblastoma-derived microglial C6 cells (ATCC-CCL-107).

The polyphenol content of Calotropis procera leaf has anti-cancer properties. Electrochemical methods were used to test Calotropis procera aqueous extract against glioblastoma cell lines (LN-18) as a cytosensor, and its possible mechanism for DNA binding was investigated using a graphite/poly(allylaminehydrochloride)/nanotube-graphene composite/polypyrrole/deoxyribonucleic acid modified electrode (Nalini et al. 2016).

Gastric cancer

Gastric cancer is a tumor of the stomach. The rate of new cases of gastric cancer is 7.1 per 100,000 men and women per year and the death rate is 2.8 per 100,000 men and women per year. Its 5-year relative survival is 33.3% (National Cancer Institute). Regarding gastric cancer, this review illustrates 5 plants cultivated in Egypt with anti-cancer activities through various mechanisms against 3 different Human gastric cancer cell lines including AGS, SGC-790, and MGC-803.

Ginkgo biloba exocarp polysaccharides (GBEP) were studied for their anticancer activity against human gastric cancer SGC-7901 cells in 30 patients with gastric cancer. It was found that GBEP can inhibit and induce differentiation and apoptosis of tumor cells by its effects on the expression of c-myc, bcl-2, and c-fos genes (Xu et al. 2003).

Gold nanoparticle (AuNP) synthesized from Nigella sativa seed extract exhibited significant cytotoxic activity against human gastric adenocarcinoma (AGS) cells by significantly upregulating intracellular apoptotic signaling molecules, such as Caspase 9/Caspase 3, p53, and Bcl-associated X protein (Bax) (Dhandapani et al. 2021).

Lymphoma

Lymphomas are a type of cancer that begins in the lymphatic system. Lymphomas are the sixth most common form of cancer overall. There are two main types of lymphoma: non-Hodgkin and Hodgkin lymphoma. The incidence of non-Hodgkin lymphoma is 19.0 per 100,000 men and women per year while in Hodgkin lymphoma, it is 2.6 per 100,000 men and women per year (National Cancer Institute). This review illustrates 3 Egyptian medicinal plants that showed anti-cancer activities through various mechanisms against 2 different human lymphoma cancer cell lines including U-937, BJAB, and Raji. It was also used against L5178Y, a mouse lymphoma cell line.

Neuroblastoma

Neuroblastoma is the most common extracranial solid tumor in childhood. It arises from immature nerve tissue in the adrenal glands, neck, chest, or spinal cord. The incidence is 10.54 cases per 1 million per year in children younger than 15 years (Smith et al. 2014). Regarding neuroblastoma, this review illustrates 3 Egyptian plants that showed anti-cancer activities through various mechanisms against 2 cell lines including SK-N-AS, SH-SY5Y, and a stage 8 neuroblastoma cell line.

Gallbladder cancer

Gallbladder cancer is a rare cancer that is usually diagnosed late due a to lack of early signs and symptoms (National Cancer Institute). The incidence of gallbladder cancer in the US is 1.4 per 100,000 among women and 0.8 among men (Rawla et al. 2019b). This review illustrates one plant cultivated in Egypt with anti-cancer activities against GBC-SD, a human Gallbladder cancer cell line.

Liver cancer

Liver cancer is the 6th most common cancer worldwide (WCRF 2018). In Egypt, Hepatocellular carcinoma (HCC) represents about 70% of all liver tumors (Ezzat et al. 2021). In this review, we found that 45 plants in Egypt have cytotoxic effects on human hepatocellular carcinoma (HePG2) and (Huh7), hepatoma (Hep3B), (Bel-7402), (SMMC-7721), and nontumorigenic fetal hepatic cell line (WRL-68).

Several plant extracts showed promising results for the prevention of liver cancer. Methanolic extract of Nigella sativa showed a chemo-preventive effect on the development of liver cancer due to its modulation of the energy metabolic pathways (such as glycolysis) that may be involved in hepatocarcinogenesis (Abdel-Hamid et al. 2013). Also, ethanolic Moringa peregrina leaf (MPLE) and bark extract (MPBE) anti-obesity and hepatoprotective effects in rats fed a high-fat diet (HFD) (Alkhudhayri et al. 2021). A non-randomized trial found that Oryza sativa extract contains anthocyanin, which may control microbiota composition and the NF-kb pathway, ultimately preserving the protective layer and tight junction of epithelial cells (Herman 2021).

Ursolic acid from Rosmarinus officinalis extract with nano-drug delivery systems was tested against hepatic carcinoma cell lines (Shao et al. 2020). Turmeric rhizome extract nanoparticles (TE-NPs) from fractions of dried turmeric (Curcuma longa Linn.) rhizome was used as anticancer agents against human hepatoma cells, HepG2, and remarkably exhibited higher cytotoxic effect when compared with free curcumin (Auychaipornlert et al. 2022). Silver nanoparticles of Myrtus communis, Phlomis aurea Decne, Citrus sinensis, Callistemon citrinus, Schinus mole, and Catharanthus roseus were used on HepG2 liver carcinoma cell line showing anticancer activities with variable levels (Abdelhady et al. 2016; Satsangi and Preet 2016; Ali Abuderman et al. 2019; Azhar et al. 2020; Dutta et al. 2020; Hailan et al. 2022).

Lung cancer

Lung cancer is the second most common cancer worldwide. It is the most common cancer in men and the second most common cancer in women. In Egypt, lung cancer causes 1.06% of total deaths according to the data published by WHO in 2020 (Insights10 2023). There are 25 Egyptian plants studied for their anticancer effect on Lung cancer (A549, A-427, H69, H82, DMS53, DMS114, H1299, QU-DB, SK-LU-1, LLC, COR-L23, CL1-0, CL1-0-GR, H460) cell lines.

The survival benefits of Solanum Nigrum Linn (SNL), Curcumae Rhizoma (CR), and other 16 herbs were evaluated. Patients given these herbs had a longer median survival time (31 months) than the control group (19 months; P 0.001). According to bioinformatics analysis, the 18 herbs exerted anti-lung-adenocarcinoma activity primarily by (1) downregulation of some growth factor receptors, such as HGFR, EGFR, and IGFR, (2) reduction of angiogenesis not only via VEGFR and PDGFR but also via neurotransmitter functions such as dopamine and serotonin, and (3) directly inhibiting the Ras signaling pathway via Ras as well as ALK and FNTA/FNTB (Liu et al. 2021). Epidemiological studies showed that eating vegetables reduces the risk of lung cancer in humans. The chemopreventive agent phenethyl isothiocyanate (PEITC), which is released when watercress (nasturtium officinale) is chewed, is a chemopreventive agent against tobacco-induced lung cancer (Hecht et al. 1995).

Many studies have proven the efficacy of Egyptian plant nanoparticles in lung cancer. The green synthesis of silver nanoparticles (AgNPs) by Beta vulgaris extract has been demonstrated to have a cytotoxic effect on the lung cancer cell line A549 (Venugopal et al. 2017). Moreover, Ag NPs were synthesized by an aqueous extract of Citrus sinensis without the use of any toxic chemical reagents. Eco-synthesized Ag NPs was revealed as a new chemotherapeutic drug for lung carcinoma cell lines. Ag NPs had IC50 values of 82, 139, 170, 66, 62, and 50 g/mL against the cell lines NCI-H661, HLC-1, NCI-H1563, LC-2/ad, NCI-H1299, and PC-14, respectively (Chen et al. 2022). The aqueous extract of Origanum vulgare (Oregano) green synthesized Ag NPs showed a dose-dependent response against human lung cancer A549 cell line (LD50—100g/ml) (Sankar et al. 2013). The self-nano-emulsifying drug delivery system (SNEDDS) has been identified as an ideal method for increasing Curcumin oral absorption and bioavailability. In vitro cytotoxic activities against cervical cancer (Hela), liver cancer (HepG2), and large cell lung cancer (H460) cell lines revealed that the prepared curcumin nanoemulsion effectively inhibited the growth of all three cell lines with IC50 values of 8.6 µM, 14.5 µM, and 5.3 µM, respectively (Nguyen et al. 2020). Plectranthus amboinicus extracts phyto-fabricated Au NPs in vitro against lung adenocarcinoma (LAC) cells (A549 cell line). The eco-synthesized Au NPs had radical scavenger properties with cytotoxic characteristics towards the A549 cell line and an IC50 of 16.3 µg/mL in 48 h (Suresh et al. 2020). Furthermore, the synthesis of gold nanoparticles using Nigella sativa essential oil (NsEO-AuNPs) demonstrated in-vitro anti-lung cancer activity, The IC50 value revealed that NsEO-AuNPs 28.37 μg ml(-1) were significantly more effective than bulk Au 87.2 μg ml(-1) and Nigella sativa essential oil 64.15 μg ml(-1) in inhibiting A549 lung cancer cells (Manju et al. 2016). Syzygium cumini seed extract (SCSE) is used as a natural reducing and stabilizing agent for the simultaneous reduction of chloroauric acid and graphene oxide in a phyto-fabricated gold nanoparticles decorated with reduced graphene oxide nanocomposite (GO). MTT assay results indicated that Au NPs-rGO-NC had an inhibitory effect on A549 (IC50 = 51.99 μgL−1) cell lines (Kadiyala et al. 2018).

Prostate cancer

Prostate cancer is the 4th most common cancer and the second most common cancer in men (World Cancer Research Fund International 2020). In Egypt, prostate cancer is the 7th most common cancer in males with an incidence rate of about 7.2% (Ibrahim and Shash 2022). Twenty Egyptian plants were found to have cytotoxic effects on different prostate cancer cell lines (DU-145, PC-3, LNCaP, C4-2, RWPE-1, PC-3M, C4-2B, PNT2, and CA-HPV-10).

Prostate-specific antigen (PSA) levels can be elevated because of prostate cancer, benign prostatic hyperplasia, prostatic infection, or inflammation. Curcuma extract can lower PSA levels in a short period (a 30-day intake). Fifty individuals were committed to the clinical trial for a first PSA level of more than 4ng/ml. This Curcuma extract may help to prevent prostate cancer, but more research is required to assess that (Fabiani et al. 2018). Prostate cancer (CaP) risk is increased in individuals with high-grade prostatic intraepithelial neoplasia (HGPIN), which makes HGPIN a prime target for herbal chemoprotective supplements such as Zyflamend, which was formed of ten botanical extracts: Bakil's skullcap, knotweed, turmeric, ginger, holy basil, green tea, and oregano. After 18 months, 48% of the individuals showed a 25–50% reduction in PSA. There was a decline in serum C-reactive protein. Immunoreactive staining showed that the 18-month samples had less NF-B. Since 13.3% (2 of 15) of the individuals in these studies had CaP at 18 months, more research is necessary to assess these medications in patients who are at risk for the condition (Capodice et al. 2009). Green tea's antineoplastic benefits in patients with androgen-independent prostate cancer were investigated in a phase II experiment. Green tea had minimal antineoplastic effects in individuals with androgen-independent prostate cancer, as measured by the decrease in PSA values (Jatoi et al. 2003). Enterolactone and enterodiol, mammalian lignans produced from flaxseed, sesame seeds, kale, broccoli, and apricots, may inhibit prostate cancer progression via VEGF-associated mechanisms (Azrad et al. 2013). A phase II trial using Artemisia annua (AA) decaf coffee demonstrated a reduction in rising PSA levels in men with biochemical recurrence of prostate cancer (Myint 2022). A phase II clinical study was done for males with increasing PSA following surgery or radiation. Pomegranate juice phytochemicals induce a considerable delay in PSA doubling time, as well as apoptosis, and oxidative stress (Pantuck et al. 2006). Moreover, another clinical trial proved that pomegranates slowed prostate cancer proliferation through prolonged prostate-specific antigen (PSA) doubling times. It was expected that pomegranate extract taken orally would reduce tissue 8-hydroxy-2'-deoxyguanosine (8-OHdG) (a DNA damage marker), an oxidative stress biomarker (Freedland et al. 2013). Pomegranate fruit extract (PFE) immunohistochemistry investigations indicated decreases from baseline in 8-OHdG and androgen receptor expression in prostate tumor-associated cells (Jarrard et al. 2021). Curcumin nanoparticles by wet-milling approach were tested in vitro against prostate cancer cell line 3 (PC3) (E% = 59.66%). The long term use and the safety of nanoparticle-based therapeutics are still questionable.

Skin cancer (Melanoma)

Skin cancers are the most common group of cancers worldwide. More than 1.5 million new cases were estimated in 2020 (Arnold et al. 2022). In Egypt, skin cancer is uncommon as it represents only 5% of the malignant tumors of the body (Hussein 2005). In this review, we found that 11 Egyptian plants were studied for their anti-cancerous effect on skin cancer cell lines (UACC-375, B16F10, A375, C32, MDA-MB-435, A431, UACC62). Capsicum annuum, Ailanthus excelsa, Panax quinquefolius, and Bauhinia variegate were tried on skin cancer in mice. AgNPs from Trigonella foenum‐graecum (TFG) seed extract were assessed for their anticancer activity against skin cancer cell line A431. The results showed more than 50% reduction in the cancerous cells growth confirming its anticancer and antioxidant activity. Also, it was observed that the anticancer activity increases with the increase in TFG‐AgNPs concentration (Goyal et al. 2018).

Thymoquinone (TQ), the active compound from Nigella sativa was formulated as TQ-Loaded PLGA nanoparticles and was evaluated for its anticancer activity against human melanoma cancer cells. High cell toxicity was observed in melanoma cells due to the rapid and sustained release of TQ from the NPs. However, further investigation is needed as stability problems of the active ingredient were addressed in this study (Ibrahim et al. 2020).

Mouth cancer

The risk of developing oral and oropharyngeal cancer is about 1.7% in males and 0.71% in females (American Cancer Society 2021). Oral cancer deaths present 0.15% of all deaths in Egypt according to data published by WHO. We found that three Egyptian plants (Gingko biloba, Lawsonia inermis, and Artemisia annua) were tried for their anti-cancerous effect on oral squamous cell carcinoma cell lines (HSC-2, HSC-4, Ca9–22, SCC-1483, SCC-25, and SCC-QLL1).

Considering nanotechnology application in oral cavity cancers, essential oils as active ingredients of lipid nanocarriers were used as chemo-therapeutic agents against oral cavity cell line (UMSCC1) (Sertel et al. 2011; Severino et al. 2015). Also, a novel strategy of nanosized herbal Plectranthus amboinicus, Phyllanthus niruri, and Euphorbia hirta treated TiO2 nanoparticles for anticancer activities on KB oral cancer cells (Maheswari et al. 2021).

Colon\ colorectal cancer

Colorectal cancer (CRC) is now the world's third greatest cause of cancer mortality. Its prevalence is gradually increasing in developing countries. CRC is a kind of colorectal adenocarcinoma that develops from the glandular, epithelial cells of the large intestine. Cancer develops when specific epithelial cells acquire a succession of genetic or epigenetic alterations that give them a selective advantage (Rawla et al. 2019a). CRC is more frequent in males than women and is three to four times more common in industrialized countries than in underdeveloped countries. The age-standardized (global) incidence rates per 100,000 CRC in both sexes are 19.7, 23.6, and 16.3, respectively. Colon cancer is the fifth most lethal malignancy, with 551,000 fatalities expected in 2018, accounting for 5.8% of all cancer deaths. Meanwhile, rectal cancer is the tenth most lethal, accounting for 310,000 fatalities (3.2% of all cancer deaths). At 0–74 years, the cumulative chance of dying from colon cancer is 0.66% for males and 0.44% for women. The risk of rectal cancer is 0.46% in males and 0.26% in women. The age-standardized (global) mortality rate of CRC in both sexes is 8.9 per 100,000 by testing on the Colon cell cancer (HCT-15 andHT-29) (HCT116) (Bray et al. 2018).

There are many clinical trials conducted to study the effect of Egyptian plants on colorectal cancer (CRC). A randomized clinical trial was conducted on 32 volunteers to explore the effect of nuts and green tea extract on CRC and the results showed that those plants regulate targeted biomarkers related to colorectal cancer oncogenesis (Hu et al. 2016). Another randomized controlled trial (RCT) was conducted on 2534 patients to compare between green tea extract and placebo effect on the prevention of CRC secondary to colorectal polyps in the elderly population (Stingl et al. 2011). A randomized, double-blind, controlled trial was conducted on Thirty-five CRC patients to study the effect of pomegranate extract consumption on microRNAs expression in normal and malignant colon tissues and it appeared to affect specific colon tissue MicroRNAs but the components responsible for its effect require further research (Nuñez-Sánchez et al. 2015). Another RCT showed that pomegranate consumption decreases plasma lipopolysaccharide-binding protein levels which contributes to the onset and development of CRC (González-Sarrías et al. 2018).

Several clinical trials studied the effect of Zingiber officinale (Ginger) on CRC by different mechanisms, an RCT conducted on 30 individuals at normal and 20 individuals at increased risk for CRC for 28 days, showed that ginger had anti-inflammatory activities with significant CRC preventive potential (Jiang et al. 2013). Another RCT on 20 people at increased risk for CRC showed that ginger may increase apoptosis and reduce proliferation in the normal-appearing colorectal epithelium, but further research is needed to support these results (Citronberg et al. 2013). Two studies showed contradictory results regarding ginger’s potential to decrease eicosanoid levels by inhibiting their synthesis from arachidonic acid, one study said it was safe and tolerable but the other did not support these findings (Zick et al. 2011). More investigations are required to make a solid conclusion about these effects.

A phase II clinical trial studied the effect of combination of 5-fluorouracil/ Ginkgo biloba extract (GBE 761 ONC) in patients with advanced CRC pretreated with 5-fluorouracil only. Forty-four patients (32 evaluable for response) participated in the study and only 2 patients showed partial response after the first cycle of treatment (Hauns et al. 2001). Another randomized, double-blind, placebo-controlled Phase II trial of Artemisia annua for CRC was conducted on 20 patients, 9 taking oral artesunate and 11 taking placebo. The results showed that artesunate has anti-proliferative effects and is well tolerated (Krishna et al. 2015; von Hagens et al. 2017; Jill 2021; Myint 2022).

Two studies showed the effect of C. citrinus leaves extract on CRC in rats. Results indicated that this extract may have a chemo-preventive effect against colon cancer by inducing antioxidant enzymes and reducing damage of oxidative stress. The extract reduced the size of the tumor, the number of aberrant crypt foci, and the crypt multiplicity (López-Mejia et al. 2019; López-Mejía et al. 2021).

Several studies have been conducted to explore the effect of nanoparticles of Egyptian plants on colorectal cancer cells. One study found that iron nanoparticles from rosemary extract could be more toxic on 4T1 and C26 cancer cell lines than total extract (Farshchi et al. 2018). Another study showed that Nano-liquid chromatography-orbitrap ms-based quantitative proteomics of carnosol and carnosic acid from rosemary herb can protect against HT-29 colon cancer cells (Valdés et al. 2017). Capsaicin-loaded self-nano emulsifying drug delivery system (SNEDDS) was found to inhibit the proliferation of HT-29 colorectal cancer cells 3.6 fold more than plain capsaicin (Bhagwat et al. 2021). Also, silver nano-spheres using zingiber officinale root extract were tested against colon cancer (HCT116) cells and showed anti-cancerous properties (Ramya et al. 2020). One study found that curcuminoids loaded poloxamer 188-based nano emulsion induces apoptosis in five colorectal cancer cell lines (CP1–CP5) (Chen et al. 2011). Another study found that polymer-encapsulated curcumin nanoparticles have anti-tumor activity on cancer cells (HT29) and (HeLa) (Kyung et al. 2009). Selenium nanoparticles from the Trigonella foenumgraecum plant cause > 50% inhibition of COLO-205 cell proliferation and could be a promising material for biomedical applications (Pansare et al. 2016). Silver nanoparticles from Phlomis species growing in Egypt showed cytotoxic activity against HCT-116 cancer cell line (Abdelhady et al. 2016). Also, gold nanoparticles from Citrus sinensis showed cytotoxicity against colon cancer cell lines (colo 320DM and Ht29) (Randive et al. 2020; Dutta et al. 2020; Chen et al. 2022).

Cervical cancer

Cervical cancer is the fourth most frequent female cancer worldwide, and it poses a significant global health concern (Bray et al. 2018). The most prevalent histological subtypes are squamous cell carcinoma and adenocarcinoma, which account for roughly 70% and 25% of all cervical malignancies, respectively (Small et al. 2017).

There are applications for nanotechnology for targeting cervical cancer as one of these studies mentioned that the nano-formulation of curcumin could reduce the expression of E6 and E7 oncogenes and increase P53 and Rb tumors. Under the influence of nano curcumin treatment, Gene and protein expression analysis showed the up-regulation of P53 and Rb factors and the downregulation of E6 and E7 (Sadeghi et al. 2022). Pd–Ag bimetallic nanoparticles were also successfully prepared by the green method by using Nigella sativa extract as a reducing and stabilizing agent. Pd–Ag NPs showed high toxic effects against MDA-MB-231, ISH, and HeLa cancer cells. Pd–Ag NPs have the potential for use in medicine (Gulbagça et al. 2022). Photosynthesized gold nanoparticles are another application which is from Catharanthus roseus -by in vitro model- induce mitochondrial-mediated apoptotic signaling pathways via reactive oxygen species (ROS) induced cytotoxicity in a cervical cancer cell line (HeLa). Exposure to Catharanthus roseus Photosynthesized gold nanoparticles CR-AuNPs for 24 h induced cleavage of caspase-3. These findings suggest that CR-AuNPs contribute to apoptotic cell death in human cervical cancer (HeLa) cells (Ke et al. 2019).

Pancreatic cancer

Pancreatic cancer is the 14th most frequent malignancy and the 7th leading cause of cancer death worldwide (McGuigan et al. 2018). Worldwide incidence and mortality rates of pancreatic cancer correlate with increasing age and are slightly more common in men than in women (Bray et al. 2018). Although the causation of pancreatic cancer is complicated and multifaceted, cigarette smoking (Bosetti et al. 2012) and a family history of the disease are the most common (Klein et al. 2004). Pancreatic cancer is classified into two types: pancreatic adenocarcinoma, which is the most prevalent (85% of cases) and develops in the pancreatic exocrine glands, and pancreatic neuroendocrine tumor (PanNET), which is less common (less than 5%) and arises in the pancreatic endocrine tissue (Hidalgo et al. 2015). Some Egyptian medicinal plants are showing anti-cancer effects against MIA PaCa2, AsPC-1, PANC-1, PANC28, BxPC-3, and HUVECs pancreatic cell lines.

Ovarian cancer

Ovarian cancer is the third-ranked gynecologic cancer (Bray et al. 2018). It has the worst prognosis and the highest mortality rate (Coburn et al. 2017). Ovarian cancer mortality rate is caused by asymptomatic growth of the tumor, delayed symptoms appearance, and lack of screening that results in its diagnosis in the advanced stages. Thus, ovarian cancer is called the silent killer (Caan and Thomson 2007). Non-Hispanic white women had the greatest ovarian cancer prevalence (12.0 per 100,000), followed by Hispanic (10.3 per 100,000), non-Hispanic black (9.4 per 100,000), and Asian/Pacific Islander women (9.2 per 100,000) (Torre et al. 2018). However, due to disparities in access to diagnostic and treatment services, ovarian cancer mortality follows a distinct pattern, with African people having the greatest death rate (Chornokur et al. 2013). Our study illustrates plants that showed anti-cancer activities through various mechanisms against SK-OV-3 (human ovarian, (CHO-1) cells ovarian cell line. In a phase I dose-escalation study, Artemisia annua (Aa) decaffeinated coffee is used in advanced ovarian cancer patients who have completed front-line carboplatin and paclitaxel chemotherapy. Biomarkers of tumor progression or recurrence are to be followed (Jill 2021). Gold nanoparticles (AuNPs) of Artemisia annua were used against the human ovarian cancer cell line (A2780) and the findings suggest that AuNP-loaded niosomal formulation is considered a promising and suitable targeted system for improving anti-tumor activity against A2780 cells (Amale et al. 2021).

Osteosarcoma

Osteosarcoma OS is the most common primary malignancy of bone in children and a high-grade primary skeletal malignancy characterized by spindle cells of mesenchymal origin depositing immature osteoid matrix (Sissons 1976). The rates of occurrence vary according to age, race, gender, and a variety of other characteristics. Male mortality rates range from 3–5 per million to 2–4 per million worldwide. Showing plants have toxic effect against bone cancer cells lines:(OST), (MG63), OSACA-8 and OSCA-40, HOS and MG63.

Renal cancer

Renal cancer is the world's 13th most frequent cancer, accounting for 2.4% of all malignancies, with over 330,000 new cases identified each year. Men have a two-fold greater incidence of kidney cancer than women (Oeyen et al. 2019). Table 1 presents some plants which show anti-cancer effects on renal cell lines A498, Caki-2, ACHN,786-0, Caki-1, and TK10.

Bladder cancer

Bladder cancer is the fourth most frequent disease in males and the eighth most common cancer in women. Ovarian cancer is the fifth most prevalent malignancy in males worldwide. It affects men four times more than women. We illustrate Egyptian medicinal plants with anti-cancer effect against (T-24) and Bladder carcinoma ECV-304 cell line.

Brain cancer

Brain cancer is a mass of tissue in which cells proliferate and replicate uncontrollably, unregulated by normal cell processes. There are several types of brain illnesses, and it is believed that one in every six persons is affected by these disorders (Roda and Bottone 2022). The common pathways of neuroinflammation, tumor microenvironment, and BBB leakage status that have been found to promote tumor initiation, invasion, and progression are frequently mediated by the dysregulation of a variety of channel proteins and ion pumps by testing on brain cell line (PC12) (Brandalise et al. 2020).

Fibrosarcoma

Fibrosarcoma are malignant tumors made out of fibroblasts with varied quantities of collagen synthesis and a "herringbone" architecture (Davis et al. 2022). Our study illustrates Egyptian plants that showed anti-cancer activities against Fibrosarcoma (HT-1080) and mouse fibroblast (3T3) cell lines.

Pharynx cancer

Silver nanoparticles (Ag-NPs) from Beta vulgaris extract showed anticancer activity against pharynx (Hep-2) cancer cell line by inducing apoptosis. The results of the study proposed that Ag-NPs can be used as an anticancer agent for various cancer types. However, in vivo examination is needed to explore the effect of these nanoparticles inside human bodies (Venugopal et al. 2017).

Adrenal gland cancer

Copper nanoparticles green synthesized from Nigella sativa L. seed aqueous extract were studied for their cytotoxic activity against the adrenal phaeochromocytoma (PC12) cell line. It was found that these nanoparticles suppressed methadone-induced cell death in phaeochromocytoma PC12 cells (Yan et al. 2020).

Endometrial cancer

Palladium-silver nanoparticles (Pd–Ag NPs) using the extract of Nigella sativa seeds were used against human endometrial carcinoma cells and it promises that Pd–Ag NPs may play a therapeutic role in complications related to cancer (Gulbagça et al. 2022).

Mechanisms of anticancer medicinal plants, which are growing in Egypt

Cell cycle checkpoint inhibitors

The cell cycle refers to the process by which a cell duplicates its whole cellular content during interphase (SubG1, G0/G1, S, and G2) and divides during the M phase (Matthews et al. 2022). Cell cycle checkpoints act as DNA surveillance mechanisms, preventing the accumulation and spread of genetic errors during cell division (Barnum and O’Connell 2014). Many medicinal plants play a critical role as checkpoint inhibitors in cancerous cells. The main active constituent of Ammi majus, xanthotoxin, inhibited HepG2 cell proliferation via cell cycle arrest at the G2/M phase and induction of apoptosis (Issa et al. 2022). Phlomis essential oil induced apoptosis in HepG2 cells by increasing cell accumulation in the sub G1 and G2/M phases of the cell cycle, decreasing the S and G0/G1 phases, activating caspases-3 and-9, and inhibiting cyclin-dependent kinase-2 (CDK2), which play critical roles in the regulation of cell cycle progression and are negatively regulated by CDK inhibitors. By using a colorimetric assay, P. aurea oil significantly reduced CDK2 activity in HepG2 cells. Docking was executed on the major chemical constituents of P. aurea oil, which were germacrene-D, trans—farnesene, limonene, and -pinene. Germacrene-D demonstrated good binding to the CDK2 receptor pocket via hydrophobic interactions of its alkyl side chains (Torky et al. 2021). Citrus sinensis active constituents 5HPMF and 5HHMF, which are monomethylated PMFs, suppress lung cancer cell growth by accumulating cell populations in the sub-G0/G1 phase.

The increased sub G0/G1 cell population revealed DNA fragmentation caused by Poly (ADP-ribose) polymerase (PARP) cleavage (Xiao et al. 2009). The ethanolic extract of Moringa peregrina revealed a high proportion of cells in the sub-G0 phase due to nuclear DNA fragmentation caused by decreased poly-ADP-ribose polymerase-1 protein expression (PARP-1). In addition, compared to the control, the proportion of cells in the G0/G1, S, and G2/M phases was significantly decreased. This outcome revealed that Moringa peregrina extract induced apoptosis in cervical and prostate cells by increasing caspase-3 mRNA expression, decreasing Bcl-2 mRNA expression, and decreasing ATP levels (Abou-Hashem et al. 2019). In CCRF-CEM leukemia cells, Withania obtusifolia, Jasonia candicans, Centaurea lippii, and Pulicaria undulata were identified as promising cytotoxic agents, which cause cell cycle arrest in the G2/M phase. Withania obtusifolia methanol extract demonstrated significant cytotoxic activity, with a low IC50 value of 0.79 µg/ml. Furthermore, it inhibited cell proliferation, increased the G2/M cell cycle phase, and decreased the S-phase. The cytotoxic mode of action was illustrated by Western blot analysis, which used increased PARP cleavage as an apoptosis marker (Hegazy et al. 2019). Treatments with Artemisia annua extract and artemisinin impair cellular distribution in different Osteosarcoma cell cycle phases. Pure artemisinin, but not Artemisia annua extract, caused a significant decrease in G0/G1 cells, followed by a significant increase in sub-G0/G1 cells in the OSCA-8 cell line. Both treatments had a significant influence on cell distribution in OSCA-40, with a significant decrease in G0/G1 cells and a significant increase in sub G0/G1 cells. The hydroalcoholic extract of Artemisia annua is cytotoxic, causing an increase in total iron, accumulation of lipid peroxides, and a "ballooning" death phenotype, indicating ferroptosis activation in osteosarcoma cell lines (Salaroli et al. 2022). Panax quinquefolius Saponins inhibited (PQS) prostate cancer cell line (DU145) and caused cell cycle arrest in the G1 phase. PQS treatment for 24 h reduced DU145 cell invasion and migration significantly. PQS increased the expression of p21, p53, TMEM79, ACOXL, ETV5, and SPINT1 while decreasing the expression of bcl2, STAT3, FANCD2, DRD2, and TMPRSS2 (He et al. 2021). Cakile maritima According to the Annexin-V assay, cytotoxicity involved the induction of G2/M phase arrest in targeted human colon cancer (HCT-116), human breast cancer (MCF-7) cells, as well as the induction of apoptosis in both cell lines. Apoptosis was investigated in MCF-7 and HCT-116 cells treated with ethanolic extracts using RT-PCR, which revealed an increase in proapoptotic genes P53, BAX, Capase-3,6,7,8,9 and a decrease in the antiapoptotic gene (BCL-2) after treatment (Tawfik et al. 2023). Curcumin caused melanoma cell cycle arrest at the G2/M phase, through downregulation of NF-B activation, nitric oxide synthase, and upregulation of tumor suppressor gene as p53, p21, p27 (Zheng et al. 2004). Cinnamon induced a cytotoxic effect through stimulation of cyclin B1 expression, suppression of Cdc25B phosphatase, and caused G2/M cell cycle arrest (Jeong et al. 2003; Shin et al. 2006). Figure 2 illustrates the medicinal plants cultivated in Egyptian, acting on specific cell cycle phases.

Fig. 2
figure 2

Mechanisms of medicinal plants cultivated in Egyptian, acting on specific cell cycle phases

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Immune checkpoint inhibitors

Immune checkpoint inhibitors function by inhibiting regulatory proteins. Checkpoint proteins, such as PD-L1 on tumor cells and (PD-1, and CTLA-4) on T cells, aid in the regulation of immune responses. By preventing PD-L1 from binding to PD-1 with an immune checkpoint inhibitor (anti-PD-L1 or anti-PD-1) T cells can eradicate cancer cells. Terpenes as cannabidiol decreased the expression of PD-L1 by either pancreatic cancer or pancreatic stellate cells through a PAK1-dependent pathway (Yang et al. 2020). Human studies have shown that green tea catechin has cancer-preventive properties by inhibiting PD-L1 expression in non–small-cell lung cancer cells and suppressing both interferon (IFN) -γ- and epidermal growth factor (EGF) by epigallocatechin gallate (EGCG) (Rawangkan et al. 2018).

Curcumin and apigenin inhibited tumor growth and promoted apoptosis in melanoma cells (A375 cell line). Flavonoids, particularly apigenin, dramatically suppressed IFN-γ-induced PD-L1 induction, with corresponding decreases in STAT1 phosphorylation (Xu et al. 2018). Furthermore, apigenin reduced IFN-γ-induced PD-L1 expression in triple-negative MDA-MB-468 BC cells (Coombs et al. 2016). Luteolin has be tested in vitro and in vivo as an anticancer vaccination adjuvant in melanoma. Luteolin was reported to stimulate the PI3K-Akt pathways in APCs (Antigen Presenting cells), stimulate APC activation, promote CTL (Cytotoxic T Lymphocyte) responses, and suppress regulatory T cells (Tian et al. 2021). Luteolin also inhibits HIF-1 expression levels in breast and colon cancer (Monti et al. 2020). Apigenin and luteolin both dramatically inhibited lung cancer growth in KRAS mutants through downregulation of IFN-γ induced PD-L1 expression through inhibiting STAT3 phosphorylation. In vivo experiments revealed that apigenin/luteolin has a synergistic effect with PD-1 antibodies in the treatment of NSCLC with KRAS mutation (Jiang et al. 2021). Curcumin cytotoxicity is caused by decreased PD-L1 expression through inhibition of STAT3 phosphorylation in tongue squamous cell carcinoma (Liao et al. 2018). Furthermore, curcumin combined with total ginsenosides inhibited TLR4/ NF-κB signaling pathway angiogenesis and decreased PD-L1 protein expression in HepG2 hepatocellular cells (Deng et al. 2020). Anthocyanins such as cyanidin-3-O-glucoside, delphinidin-3-O-glucoside, delphinidin chloride, and gallic acid have been shown in silico experiments to reduce the binding of PD-L1 to PD-1, leading in T cell stimulation in the tumor microenvironment (Mazewski et al. 2019). In crizotinib-resistant cells, silibinin-induced STAT3 suppression worked synergistically with crizotinib to reverse its resistance. Furthermore, silibinin suppressed PD-L1 expression as well as EMT regulators (e.g., SLUG, VIM, and CD44) in crizotinib-resistant cells (Cuyàs et al. 2016). In nasopharyngeal cancer, silibinin can decrease PD-L1 expression by disrupting the hypoxia-inducible transcription factor HIF-1/LDH-A-mediated cell metabolism (Sellam et al. 2020).

In MDA-MB231 cells, hesperidin decreased cell proliferation. Furthermore, hesperidin suppressed the overexpression of PD-L1 in cancer cells via suppressing Akt and NF-κB signaling (Kongtawelert et al. 2020). In oral cancer cells, hesperidin inhibited PD-L1 expression by suppressing STAT1 and STAT3 phosphorylation (Wudtiwai et al. 2021).

Gallic acid (GA) inhibits colorectal cancer (CRC) growth and improves PD-1 antibody by suppressing the PD-L1 expression via STAT3 phosphorylation (Deng et al. 2022). In non-small-cell lung cancer cells, GA blocked EGFR and inhibited EGF binding, inhibiting PI3K/AKT pathway, and decreasing PD-L1 expression (Kang et al. 2020). Resveratrol (RSV) alters N-linked glycosylation and inhibits the cell membrane translocation of PD-L1. Furthermore, in silico experiments suggested that RSV might cause PD-L1 dimerization, which could directly disrupt the PD-1/PD-L1 interaction (Verdura et al. 2020). In the mouse lung cancer model, lycopene can potentiate anti-PD-1 antibodies to alter PD-L1 expression. Lycopene also inhibited IFN-induced PD-L1 expression in lung cancer cells by activating JAK2/STAT3 signaling, while suppressing AKT signaling (Jiang et al. 2019). Ginsenosides, a triterpenoid saponin, is reported to be a potential anti-PD-L1 drug for the treatment of chemotherapy-resistant NSCLC. Furthermore, PD-L1 deficiency was linked to Akt and NF-B signaling pathway deficiency (Jiang et al. 2017). Panaxadiol, a triterpenoid sapogenin isolated from Panax ginseng roots, suppressed PD-L1 expression in colon cancer through blocking HIF-1 and STAT3 signals (Wang et al. 2020b). Cinnamon extract inhibited tumor progression by downregulating tumor-associated growth factors such as EGF, VEGF-, TGF-, Cox-2, HIF-1, and neo-vascularization, while enhancing CD8 + T cell cytolytic activity (Kwon et al. 2009). The mechanisms of medicinal plants cultivated in Egyptian, acting on the immune checkpoints are summarized in Fig. 3.

Fig. 3
figure 3

Mechanisms of medicinal plants cultivated in Egyptian, acting on the immune checkpoints

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Apoptosis

Glycyrrhiza glabra L chloroform and methanol fractions had potent antioxidant and cytotoxic effects in HeLa and HepG2 cancer cells via up-regulating pro-apoptotic proteins caspase-8, caspase-3, and down-regulating anti-apoptotic proteins (Bcl-2). Rutin and gallic acid are the flavonoid and phenolic contents of the methanol fraction (Hejazi et al. 2017). Rutin had anti-neuroblastoma activity via inducing G2/M arrest in the cell cycle by suppressing BCL2 expression and the BCL2/BAX ratio (Chen et al. 2013). Furthermore, rutin induced apoptosis through upregulation of caspase-3, caspase-9, and BAX (Pandey et al. 2021). Glabridin, a prenylated isoflavonoid derived from the roots of Glycyrrhiza glabra L., suppressed cell growth in acute myelogenous leukemia cell lines. Moreover, glabridin caused apoptosis by activating caspases-3, -8, and -9 and cleaving PARP (Huang et al. 2014). Glycyrrhizic acid-induced G1 phase cell cycle arrest by decreasing proteins such as cyclin D1, D2, D3, E1, and E2. Glycyrrhizic acid increased the levels of Bax, cleaved PARP, and pro-caspase-3, -8, and -9, but didn’t affect their cleavage patterns. Furthermore, Glycyrrhizic acid would inhibit PI3K/AKT phosphorylation (Wang et al. 2020a). Gallic acid-induced apoptosis of non-small-cell lung cancer NCI-H460 cells at the G2/M phase through activation of caspase-8, -9, and -3 increases the mitochondrial release of cytochrome c and AIF. Furthermore, Gallic acid suppressed BCL2 and increased BAX (Ji et al. 2009). Two isomers of pregnane steroids isolated from Melia azedarach L. induced apoptosis in breast cancer by increasing the ratio of BAX/bcl-2 (Ervina et al. 2021). Ricinus communis L. fruit extract (RCFE) contained ricinine, p-coumaric acid, epigallocatechin, and ricinoleic acid, which showed cytotoxic activities in breast cancer. RCFE-induced apoptosis by decreasing Bcl-2 and increasing pro-apoptotic Bax and caspase-7 expressions, as well as PARP cleavage (Majumder et al. 2019). Apoptosis induced by ricin, a protein isolated from Ricinus communis seeds, was caused by upregulation of caspase-9 and caspase-3 (Herawati et al. 2022). Ginkgo biloba exocarp polysaccharides (GBEP) induced apoptosis of human gastric cancer through attenuation of the expression of c-myc, bcl-2, and c-fos genes (Xu et al. 2003). Kaempferol and quercetin isolated from Ginkgo biloba leaves have been reported to induce apoptosis via activation of caspase-3 in oral cavity cancer cells (Kang et al. 2010b). 8-Methoxypsoralen (8-MOP) is a furanocoumarin isolated from Ammi majus L. that induces apoptosis in several human cancer cell lines, including neuroblastoma (SK-N-AS) and metastatic colon cancer (SW620), by suppressing AKT, downregulating Bcl-2, increasing Bax, and activating caspases -8, -9, and -3 (Bartnik et al. 2017). Ellagitannins isolated from Lawsonia inermis leaves showed a cytotoxic effect on human oral squamous cell carcinoma cell lines. Tellimagrandin II exhibited the greatest cytotoxicity by increasing the amount of cleaved poly (ADP-ribose) polymerase 1 (Orabi et al. 2021). Thymoquinone (TQ) isolated from Nigella sativa significantly increased the number of pre-G1 (apoptotic) cells; G2/M arrest in osteosarcoma was associated with p21 upregulation. TQ showed the activation of caspases 8, 9, and 3. TQ revealed a three-fold increase in the Bax/Bcl-2 ratio and the induction of p53 (Roepke et al. 2007). New triflavanone and dicoumarinyl ethers isolated from Thymelaea hirsuta daphnoretin methyl ether, and acetyldaphnoretin stimulated apoptosis of breast cancer, resulting in the Pre-G1 stage of the cell cycle arrest by stimulation of BAX and caspase-9, and attenuation of BCL2 (Elhady et al. 2021). Diosgenin isolated from fenugreek caused HEp-2 cells' deaths in S phase and G2/M phase by increasing the apoptotic ratio (Bax/Bcl-2) by 1.6-fold and activating caspase-3 and -9 by 1.6- and 1.2-fold, respectively. PARP cleavage is aided by diosgenin (Corbiere et al. 2004). The rosemary extract and diterpenes suppressed cell viability and caused apoptosis and cell cycle arrest in the G2/M phase (Chan et al. 2021). Rosemary diterpenes: 1. carnosic acid causes apoptosis by inhibiting Bcl-2, increasing Bax protein expression and cytochrome c release, and activating caspase-8, -9, -3, -7, and PARP cleavage. 2. Carnosol induces apoptosis through attenuation of Bcl-2 expression, activation of caspase-8, -9, and -3, PARP cleavage, upregulation of Bax levels, and mitochondrial membrane depolarization. 3. Rosmanol causes apoptosis by increasing Fas and FasL, cytochrome c release, and PARP cleavage (Petiwala and Johnson 2015). Carvacrol isolated from thyme, black cumin, and oregano caused colon cancer cell cycle arrest at the G2/M phase and suppressed cyclin B1 expression. Moreover, carvacrol induced apoptosis by downregulating Bcl-2 and upregulating the expression of Bax (Fan et al. 2015). Hispidulin isolated from Onopordum alexandrinum induced apoptosis by activating the mitochondria-mediated pathway via an increased ratio of Bax/Bcl-2, cytochrome c release, and caspase-3 sequential increase (Gao et al. 2014; Ashaq et al. 2021). Naringenin, isolated from Artemisia argyi, activates caspase-3, caspase-9, caspase-8, and Bax expression in cancer cells (Li et al. 2008; Faramarzi et al. 2022). Jaceosidin, a flavonoid isolated from Artemisia vestita and Artemisia argyi, causes apoptosis in renal carcinoma cells by activation of Bax and caspase-3, cleavage of PARP, the release of cytochrome c, and attenuation of Mcl-1 and c-FLIP expression (Lee et al. 2005; Woo and Kwon 2016). Apigenin-induced apoptosis in human lung cancer cells by activating caspases 3, 8, and 9, as well as Bax, and inhibiting BCL-2 (Xu et al. 2018). Eugenol is isolated from nutmeg, basil, cinnamon, and clove. Eugenol activated caspase-9, -3 PARP cleavage, and Bax, decreased Bcl2, and released cytochrome C. Further, eugenol suppressed the expression of MMP-2 and MMP-9, VEGF, and VEGFR1, and increased the expression of TIMP-2 and RECK (Jaganathan and Supriyanto 2012). Sesamol in sesame seeds exerts cytotoxic activity towards human non-small cell lung adenocarcinoma (SK-LU-1) by activation of caspases 8, 9, 3, and 7 and cleavage of PARP (Siriwarin and Weerapreeyakul 2016). Capsaicin (CPS), isolated from green and red peppers, induces apoptosis in renal carcinoma by activating c-myc, FADD, and Bax expression while suppressing Bcl2 expression, finally activating the caspase-3, -8, and -9 cascades (Liu et al. 2016). Emodin increased the expression of p53, p21, Bax, cyclin E, caspases 3, 8, and 9, as well as cleaved poly (ADPribose) polymerase (PARP). However, the protein expression of Bcl2, cyclin A, and CDK2 was suppressed. Emodin promotes apoptosis in hepatocellular carcinoma via the mitochondrial apoptosis cascade (Dong et al. 2018). Figure 4 shows the apoptosis cascade and the mechanism of each of the Egyptian medicinal plants.

Fig. 4
figure 4

Medicinal plants cultivated in Egyptian, with apoptotic effects. From Azzwali and Azab (2019), under the terms of the Creative Commons Attribution License

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Conclusion

In recent years, there has been a shift towards researching the medicinal properties and anticancer potential of various plant compounds, including flavonoids, phenolics, terpenoids, alkaloids, and other constituents. Our review delved into the potential of medicinal plants in Egypt to act as effective anticancer agents. These plants underwent in vivo and in vitro studies, as well as clinical trials in various stages. The data were gathered from Scopus, and PubMed databases through literature survey. We found that the most promising plants were Capsicum annuum, Camellia sinensis, Zingiber officinale, Punica granatum, and Nerium oleander as these plants showed anticancer activity in several clinical trials targeting different organs. Also, the development of nanoparticles (NPs) of these plants as a part of cancer therapeutics was investigated. The most promising plants were Rosmarinus officinalis, Curcuma longa, and Nigella sativa. Other plants’ NPs such as Beta vulgaris, Plectranthus amboinicus, Citrus sinensis, Cassia angustifolia, and Catharanthus roseus showed cytotoxic activity. Several in vivo and in vitro studies showed that gold, silver, zinc oxide, copper, iron, and platinum nanoparticles of these plants exhibited cytotoxicity as monotherapy or in combination with other cytotoxic drugs. Additional studies are necessary to investigate the efficacy and the safety of plants-based therapeutic regimens in human subjects. It is also important to further investigate the active compounds found in these plants and their mechanism of action, as this could potentially lead to a new approach to cancer prevention and treatment.