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Therapeutic potential of snake venom, l-amino oxidase and sorafenib in hepatocellular carcinoma

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Abstract

Background

Sorafenib (SOR) is the only approved molecular targeted agent for the treatment of hepatocellular carcinoma (HCC), however, its use is delayed by the recently articulated safety concerns.

Objective

The present study aimed to test the hypothesis that combining snake venoms (SVs) or its ingredient l-amino acid oxidase (LAAO) could synergistically enhance the anti-proliferative effects of SOR at low doses on liver cancer cells (HepG2) versus normal liver cells (THLE2).

Methods

The cytotoxic effects were measured on HepG2 and THLE-2 using MTT assay. Gene expression for apoptotic, inflammatory, antioxidant and cell cycle regulator genes was detected by real-time PCR. The number of cells in each cell cycle phase was determined by flow cytometry.

Results

SV, LAAO, and SOR exhibited higher cytotoxicity on HepG2 cells than THLE2 cells with the 2 combinations (2 LAAO + 3/4 SOR and 3 LAAO + 3/4 SOR) showed a potent synergistic anti-tumor effect on HepG2 while being safer on THLE-2. These 2 combinations significantly elevated the expression of apoptotic (Bax, caspase 3, 8, 9, p21), inflammatory (IL6, IL1β), and antioxidant (Nrf2 and HO-1) genes, and significantly decreased the expression of the anti-apoptotic Bcl2 and DNA topoisomerase 2-binding protein 1 (Topbp1) genes relative to the single treatment. Besides, there were a significant increase in MDA and SOD but a significant decrease in GPx and CAT activity in combined and single treatments with SOR versus the untreated control. The combined therapy also arrested HepG2 in the G2/M phase.

Conclusion

Our results suggest a novel synergistic, selective, inflammatory, and anti-proliferative effect of SV or LAAO with SOR on HepG2 cells. These 2 novel combinations could serve as a potential tool for the development of a novel therapeutic approach against HCC.

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Acknowledgements

This study was funded by authors and no other fund was received.

Author information

Authors and Affiliations

  1. Chemistry Department, Faculty of Science, Cairo University, Cairo, Egypt

    Dalia H. Mahfouz, Ghada H. Mansour & Ismail A. Abdelhamid

  2. Anatomy Department, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafr El-Shaikh, Egypt

    Mohammed A. El-Magd

  3. Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt

    Abdel Hady Abdel Wahab

  4. Zoology Department, Faculty of Science, Cairo University, Cairo, Egypt

    Emad Elzayat

Authors
  1. Dalia H. Mahfouz
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  2. Mohammed A. El-Magd
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  3. Ghada H. Mansour
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  4. Abdel Hady Abdel Wahab
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  5. Ismail A. Abdelhamid
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  6. Emad Elzayat
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Contributions

EE, AA, and IA designed the experiments; DM, ME, and GM conducted the experiments; EE, ME, and DM analyzed the data; EE, DM and ME wrote the manuscript; and all authors revised the manuscript.

Corresponding authors

Correspondence to Mohammed A. El-Magd or Emad Elzayat.

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Conflict of interest

DM declares that she has no conflict of interest. ME declares that he has no conflict of interest. GM declares that she has no conflict of interest. AA declares that he has no conflict of interest. IA declares that he has no conflict of interest. EE declares that he has no conflict of interest.

Ethical approval

Approval of the present study was obtained by the Ethics Committee of Cairo University.

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Mahfouz, D.H., El-Magd, M.A., Mansour, G.H. et al. Therapeutic potential of snake venom, l-amino oxidase and sorafenib in hepatocellular carcinoma. Mol. Cell. Toxicol. (2021). https://doi.org/10.1007/s13273-021-00151-8

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  • DOI: https://doi.org/10.1007/s13273-021-00151-8

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