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COX 2-inhibitors; a thorough and updated survey into combinational therapies in cancers

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Abstract

Cyclooxygenase (COX) enzymes are pivotal in inflammation and cancer development. COX-2, in particular, has been implicated in tumor growth, angiogenesis, and immune evasion. Recently, COX-2 inhibitors have arisen as potential therapeutic agents in cancer treatment. In addition, combining COX inhibitors with other treatment modalities has demonstrated the potential to improve therapeutic efficacy. This review aims to investigate the effects of COX inhibition, both alone and in combination with other methods, on signaling pathways and carcinogenesis in various cancers. In this study, a literature search of all major academic databases was conducted (PubMed, Scholar google), including the leading research on the mechanisms of COX-2, COX-2 inhibitors, monotherapy with COX-2 inhibitors, and combining COX-2-inhibitors with chemotherapeutic agents in tumors. The study encompasses preclinical and clinical evidence, highlighting the positive findings and the potential implications for clinical practice. According to preclinical studies, multiple signaling pathways implicated in tumor cell proliferation, survival, invasion, and metastasis can be suppressed by inhibiting COX. In addition, combining COX inhibitors with chemotherapy drugs, targeted therapies, immunotherapies, and miRNA-based approaches has enhanced anti-tumor activity. These results suggest that combination therapy has the potential to overcome resistance mechanisms and improve treatment outcomes. However, caution must be exercised when selecting and administering combination regimens. Not all combinations of COX-2 inhibitors with other drugs result in synergistic effects; some may even have unfavorable interactions. Therefore, personalized approaches that consider the specific characteristics of the cancer and the medications involved are crucial for optimizing therapeutic strategies. In conclusion, as monotherapy or combined with other methods, COX inhibition bears promise in modulating signaling pathways and inhibiting carcinogenesis in various cancers. Additional studies and well-designed clinical trials are required to completely elucidate the efficacy of COX inhibition and combination therapy in enhancing cancer treatment outcomes. This narrative review study provides a detailed summary of COX-2 monotherapy and combination targeted therapy in cancer treatment.

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Data availability

Data sharing does not apply to this article as no new data were created or analyzed in this review study.

Abbreviations

COX:

Cyclooxygenases

Ptgs2:

Prostaglandin-endoperoxide synthase 2

PGE2:

Prostaglandin E2

DMBA:

7,12-dimethylbenz[a]anthracene

EP1:

Prostaglandin E2 receptor 1

EGFR:

Epidermal growth factor receptor

MMPs:

Matrix metalloproteinases

TGF2:

Transforming growth factor 2

PI3K:

Phosphatidylinositol 3-kinase

AKT:

protein kinase B

NSAIDs:

Non-steroidal anti-inflammatory medications

ICP:

Intracranial pressure

TXA2:

Thromboxane A2

TRAILR:

Tumor necrosis factor-related apoptosis-inducing ligand Receptor

IDO:

Indoleamine 2,3-dioxygenase

BCL-2:

B-cell lymphoma 2

OS:

Overall survival

STAT3:

Signal transducers and activators of transcription 3

VEGF:

vascular endothelial growth factor

JAK-2:

Janus Kinase 2

TKI:

Tyrosine kinase inhibitor

HER2:

Human epidermal growth factor receptor 2

NSCLC:

Non-small-cell lung cancer

MDSCs:

Myeloid-derived suppressor cells

ER:

Endoplasmic reticulum

HCC:

Hepatocellular carcinoma

miRNA:

MicroRNA

ncRNAs:

Non-coding RNAs

MDR:

Multidrug resistance protein 1

NF-κB:

Nuclear factor kappa B

LRP:

low-density lipoprotein receptor-related protein-1

mTOR:

Mammalian target of rapamycin

ABCB1:

Adenosine triphosphate–binding cassette subfamily B member 1

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Acknowledgements

The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University for funding this work through a large group Research Project under grant number RGP2/420/44.

Funding

This study was supported by the deanship of Scientific Research at King Khalid University for funding this work through a large group Research Project under grant number RGP2/420/44.

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Authors and Affiliations

  1. Department of Computer Engineering, College of Computer Science, King Khalid University, Al-Faraa, Asir-Abha, Kingdom of Saudi Arabia

    Paul Rodrigues & Harun Bangali

  2. Department of Medical and Technical Information Technology, Bauman Moscow State Technical University, Moscow, Russia

    Ahmad Hammoud

  3. Department of Mathematics and Natural Sciences, Gulf University for Science and Technology, Mishref Campus, Mubarak Al-Abdullah, Kuwait

    Ahmad Hammoud

  4. Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq

    Yasser Fakri Mustafa

  5. Department of Biology, College of Education For Pure Sciences, University of Anbar, Ramadi, Anbar, Iraq

    Hussein Riyadh Abdul Kareem Al-Hetty

  6. Cardiology Department, College of Medicine, Al-Ayen University, Thi-Qar, Iraq

    Adnan Taan Alkhafaji

  7. Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India

    Maha Medha Deorari

  8. Department of Medical Laboratories Technology, AL-Nisour University College, Baghdad, Iraq

    Muataz Mohammed Al-Taee

  9. College of Medical Technique, the Islamic University, Najaf, Iraq

    Rahman S. Zabibah

  10. College of Technical Engineering, Imam Ja’afar Al-Sadiq University, Al-Muthanna, 66002, Iraq

    Ali Alsalamy

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  1. Paul Rodrigues
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Contributions

PR, HB, YFM, HRAKA-H, ATA: Conceptualization, Writing—original draft preparation. MMD, MMA-T, RSZ, AA: Conceptualization, Writing—review and editing, Visualization. AH: Conceptualization, Supervision. All authors read and approved the final manuscript.

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Correspondence to Ahmad Hammoud or Hussein Riyadh Abdul Kareem Al-Hetty.

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Rodrigues, P., Bangali, H., Hammoud, A. et al. COX 2-inhibitors; a thorough and updated survey into combinational therapies in cancers. Med Oncol 41, 41 (2024). https://doi.org/10.1007/s12032-023-02256-7

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