Abstract
Mahanimbine is a carbazole alkaloid that has been identified and isolated from several members of the Rutaceae family. Previous studies have demonstrated that alkaloids such as mahanimbine exhibit the capacity to suppress the growth and progression of cancer cells. Therapeutic side effects and the cost of management for patients with lung carcinomas demand the exploration of natural plant-based therapeutic options for this debilitating disease. The study was focused on elucidating the mechanism of inhibition of non-small-lung cancer A549 cells post exposure to mahanimbine. The preliminary investigation was centered on evaluating the cytotoxic effects of mahanimbine on A549 cells along with the exploration of pathways resulting in growth inhibition of A549 cells. Our results showed that mahanimbine restrained the growth of non-small lung cancer A549 cells substantially by activating reactive oxygen species–dependent intrinsic apoptotic pathways. Therefore, this initial study indicated that mahanimbine serves as a plausible anti-cancer therapeutical option for the treatment and management of lung cancer.
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References
Ahmad A, Ansari IA (2021) Carvacrol exhibits chemopreventive potential against cervical cancer cells via caspase-dependent apoptosis and abrogation of cell cycle progression. Anticancer Agents Med Chem 21:2224–2235. https://doi.org/10.2174/1871520621999201230201258
Ahmad A, Tiwari RK, Saeed M, Ahmad I, Ansari IA (2022) Glycyrrhizin mediates downregulation of notch pathway resulting in initiation of apoptosis and disruption in the cell cycle progression in cervical cancer cells. Nutr Cancer 74:622–639. https://doi.org/10.1080/01635581.2021.1895234
Amna U, Halimatussakdiah H, Wahyuningsih P, Saidi N, Nasution R, Astryna S (2019) Phytochemical screening and in vitro cytotoxic activity of hexane extract of temurui (Murraya koenigii (Linn.) Spreng) leaves against human cervical cancer (HeLa) cell line. IOP Conf Ser: Mater Sci Eng 523:012018.
Ansari IA, Ahmad A, Imran MA, Saeed M, Ahmad I (2021) Organosulphur compounds induce apoptosis and cell cycle arrest in cervical cancer cells via downregulation of HPV E6 and E7 oncogenes. Anticancer Agents Med Chem 21:393–405. https://doi.org/10.2174/1871520620999200818154456
Bhandari PR (2012) Curry leaf (Murraya koenigii) or cure leaf: review of its curative properties. J Med Nutr Nutraceut 1:92–97. https://doi.org/10.4103/2278-019X.101295
Birari R, Javia V, Bhutani KK (2010) Antiobesity and lipid lowering effects of Murraya koenigii (L.) Spreng leaves extracts and mahanimbine on high fat diet induced obese rats. Fitoterapia 81:1129–1133. https://doi.org/10.1016/j.fitote.2010.07.013
Brentnall M, Rodriguez-Menocal L, De Guevara RL, Cepero E, Boise LH (2013) Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis. BMC Cell Biol 14:32. https://doi.org/10.1186/1471-2121-14-32
Cancer Treatment Centers of America (2021) Lung cancer types. Last updated: May 21, 2021. Available at https://www.cancercenter.com/cancer-types/lung-cancer/types, accessed on May 28, 2021.
Chakrabarty M, Nath A, Khasnobis S, Chakrabarty M, Konda Y, Harigaya Y, Komiyama K (1997) Carbazole alkaloids from Murraya koenigii. Phytochemistry 46:751–755. https://doi.org/10.1016/s0031-9422(97)00345-2
Dahiya J, Singh J, Kumar A, Sharma A (2016) Isolation, characterization and quantification of an anxiolytic constituent - mahanimbine, from Murraya koenigii Linn. Spreng Leaves J Ethnopharmacol 193:706–711. https://doi.org/10.1016/j.jep.2016.10.014
Ismail A, Noolu B, Gogulothu R, Perugu S, Rajanna A, Babu SK (2016) Cytotoxicity and proteasome inhibition by alkaloid extract from Murraya koenigii leaves in breast cancer cells-molecular docking studies. J Med Food 19:1155–1165. https://doi.org/10.1089/jmf.2016.3767
Ju J, Gothai S, Hasanpourghadi M, Nasser AA, Ibrahim IAA, Shahzad N, Pandurangan AK, Muniandy K, Kumar SS, Arulselvan P (2018) Anticancer potential of Moringa oleifera flower extract in human prostate cancer PC-3 cells via induction of apoptosis and downregulation of AKT pathway. Phcog Mag 14:477–481. https://doi.org/10.4103/pm.pm_516_17
Kaushik N, Lee SJ, Choi TG, Baik KY, Uhm HS, Kim CH, Kaushik NK, Choi EH (2015) Non-thermal plasma with 2-deoxy-D-glucose synergistically induces cell death by targeting glycolysis in blood cancer cells. Sci Rep 5:8726. https://doi.org/10.1038/srep08726
Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, Blagosklonny MV, El-Deiry WS, Golstein P, Green DR, Hengartner M, Knight RA, Kumar S, Lipton SA, Malorni W, Nuñez G, Peter ME, Tschopp J, Yuan J, Piacentini M, Zhivotovsky B, Melino G (2009) Nomenclature Committee on Cell Death 2009. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ 16:3–11. https://doi.org/10.1038/cdd.2008.150
Li L, Huizhi L, Binu W, Xinxin D, Longjun W, Liping Y, Yingying Z (2018) Anticancer activity of mukonal against human laryngeal cancer cells involves apoptosis, cell cycle arrest, and inhibition of PI3K/AKT and MEK/ERK signalling pathways. Med Sci Monit 24:7295–7302. https://doi.org/10.12659/MSM.910702
Liou GY, Storz P (2010) Reactive oxygen species in cancer. Free Radic Res 44:479–496. https://doi.org/10.3109/10715761003667554
Mani V, MohdAzahan NS, Ramasamy K, Lim SM, Abdul Majeed AB (2021) Mahanimbine improved aging-related memory deficits in mice through enhanced cholinergic transmission and suppressed oxidative stress, amyloid levels, and neuroinflammation. Brain Sci 12:12. https://doi.org/10.3390/brainsci12010012
Martin-Cordero C, Leon-Gonzalez AJ, Calderon-Montano JM, Burgos-Moron E, Lopez-Lazaro M (2012) Pro-oxidant natural products as anticancer agents. Curr Drug Targets 13:1006–1028. https://doi.org/10.2174/138945012802009044
Nadaf S, Desai R, More T, Shinde P, Dakare S, Killedar S (2020) Antiproliferative and caspase-mediated apoptosis inducing effects of Murraya koenigii seeds against cancer cells. S Afr J Bot 132:328–337. https://doi.org/10.1016/j.sajb.2020.05.021
NavaneethaKrishnan S, Rosales JL, Lee KY (2019) ROS-mediated cancer cell killing through cietary phytochemicals. Oxid Med Cell Longev 2019:9051542. https://doi.org/10.1155/2019/9051542
Newman DJ, Cragg GM, Snader KM (2003) Natural products as sources of new drugs over the period 1981–2002. J Nat Prod 66:1022–1037. https://doi.org/10.1021/np030096l
Noolu B, Gogulothu R, Bhat M, Qadri SS, Reddy VS, Reddy GB, Ismail A (2016) In vivo inhibition of proteasome activity and tumour growth by Murraya koenigii leaf extract in breast cancer xenografts and by its active flavonoids in breast cancer cells. Anticancer Agents Med Chem 16:1605–1614. https://doi.org/10.2174/1871520616666160520112210
Pei C, He Q, Liang S, Gong X (2018) Mahanimbine exerts anticancer effects on human pancreatic cancer cells by triggering cell cycle arrest, apoptosis, and modulation of AKT/mammalian target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3) signalling pathways. Med Sci Monit 24:6975–6983. https://doi.org/10.12659/MSM.911013
Porter AG, Jänicke RU (1999) Emerging roles of caspase-3 in apoptosis. Cell Death Differ 6:99–104. https://doi.org/10.1038/sj.cdd.4400476
Qie S, Diehl JA (2016) Cyclin D1, cancer progression, and opportunities in cancer treatment. J Mol Med 94:1313–1326. https://doi.org/10.1007/s00109-016-1475-3
Ross MF, Kelso GF, Blaikie FH, James AM, Cochemé HM, Filipovska A, Da Ros T, Hurd TR, Smith RA, Murphy MP (2005) Lipophilic triphenylphosphonium cations as tools in mitochondrial bioenergetics and free radical biology. Biochemistry 70:222–230. https://doi.org/10.1007/s10541-005-0104-5
Singh UP, Bhat HR (2017) Discovery of 1,3,5-triazine based novel EGFR-tyrosine kinase inhibitor against human lung carcinoma. Ann Oncol 28:II10. https://doi.org/10.1093/annonc/mdx089.005
Tantapakul C, Phakhodee W, Laphookhieo S, Ritthiwigrom T, Cheenpracha S (2014) Cytotoxic carbazole alkaloids from the stems of Murraya koenigii. Chem Nat Compd 50:186–188. https://doi.org/10.1007/s10600-014-0909-9
Wang Y, Yu H, Zhang J, Gao J, Ge X, Lou G (2015) Hesperidin inhibits HeLa cell proliferation through apoptosis mediated by endoplasmic reticulum stress pathways and cell cycle arrest. BMC Cancer 15:682. https://doi.org/10.1186/s12885-015-1706-y
Wei M, Liu B, Gu Q, Su L, Yu Y, Zhu Z (2013) Stat6 cooperates with Sp1 in controlling breast cancer cell proliferation by modulating the expression of p21(Cip1/WAF1) and p27 (Kip1). Cell Oncol 36:79–93. https://doi.org/10.1007/s13402-012-0115-3
WHO (2021) World Health Organization factsheet on Cancer. https://www.who.int/news-room/fact-sheets/detail/cancer. Accessed 3 Feb 2022
Xie H, Zhang T, Yang N, Li Z, Liu Y (2020) Anticancer effects of mahanimbine alkaloid on the human bladder cancer cells are due to the induction of G0/G1 cell cycle arrest, apoptosis and autophagy. J BUON 25:1166–1171
Yeh CT, Huang WC, Rao YK, Ye M, Lee WH, Wang LS, Tzeng DT, Wu CH, Shieh YS, Huang CY, Chen YJ, Hsiao M, Wu AT, Yang Z, Tzeng YM (2013) A sesquiterpene lactone antrocin from Antrodia camphorata negatively modulates JAK2/STAT3 signaling via microRNA let-7c and induces apoptosis in lung cancer cells. Carcinogenesis 34:2918–2928. https://doi.org/10.1093/carcin/bgt255
Żuryń A, Litwiniec A, Safiejko-Mroczka B, Klimaszewska-Wiśniewska A, Gagat M, Krajewski A, Gackowska L, Grzanka D (2016) The effect of sulforaphane on the cell cycle, apoptosis and expression of cyclin D1 and p21 in the A549 non-small cell lung cancer cell line. Int J Oncol 48:2521–2533. https://doi.org/10.3892/ijo.2016.3444
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GH and JP contributed equally to formal analysis, investigation, and data curation. QW contributed to data analysis. XZ contributed to conceptualization, project administration, and supervision. All authors have read the final manuscript and agreed the submission.
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Hu, G., Pu, J., Wang, Q. et al. Mahanimbine Suppresses the Proliferation of Lung Cancer A549 Cells Via Inducing Intrinsic Apoptotic Pathway. Rev. Bras. Farmacogn. 33, 384–393 (2023). https://doi.org/10.1007/s43450-023-00357-y
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DOI: https://doi.org/10.1007/s43450-023-00357-y