Idarubicin-bromelain combination sensitizes cancer cells to conventional chemotherapy

Document Type: Original Article

Authors

1 Nutrition and Dietetics Department, Faculty of Health Science, Harran University, Şanlıurfa, Turkey

2 Department of Biochemistry, Medical Faculty, Gaziantep University, Gaziantep, Turkey

Abstract

Objective(s): The primary cytotoxic effects of anticancer drugs like idarubicin, a chemotherapeutic agent, are not limited to neoplastic cells; they also produce similar effects in normal cells. In this study, we hypothesized that the combination of idarubicin-bromelain could make cancer cells more susceptible to cytotoxicity and genotoxicity.
Materials and Methods: To test our hypothesis, the optimal concentrations of idarubicin and bromelain were combined and incubated in the HL-60 cancer cell line and normal human mononuclear leukocytes (PBMC) for 24, 48, and 72 hr. Cytotoxicity and genotoxicity were evaluated by measurement of ATP cell viability test, DNA damage, Caspase-3, Acridine orange/ethidium bromide (AO/EB), and DAPI fluorescent dyes in both cell types.
Results: The combination of idarubicin-bromelain significantly reduced cell proliferation in the more potent HL-60 compared to PBMC in all incubation times (P<0.05). DNA damage and Caspase-3 levels (except for 24 hr) were also higher in the HL-60 cell line in comparison with PBMC and were statistically significant (P<0.05). The percentages of apoptotic images obtained by DAPI and AO / EB morphological examination were increased in both cells, depending on the combination dose.
Conclusion: Based on these results, it can be concluded that idarubicin combined with bromelain produces more cytotoxic effects in low concentrations in comparison with when it was used per se in the HL-60 cells. Conversely, it was found that this combination in PBMC caused less cytotoxicity and less genotoxicity. Taken together, it can be said that this new combination makes cancer cells more sensitive to conventional therapy.

Keywords

Main Subjects


1. Parikh SA, Jabbour E, Koller CA. Adult acute myeloid leukemia. In: Kantarjian HM, Wolff RA, Koller CA, editors.  The MD Anderson Manual of Medical Oncology. 2nd ed. New York: The McGraw-Hill Companies, Inc; 2011. p. 15-32.
2. Li X, Xu S, Tan Y, Chen J. The effects of idarubicin versus other anthracyclines for induction therapy of patients with newly diagnosed leukaemia. Cochrane Database Syst Rev 2015; 6:10432-10684.
3. Chen B, Peng X, Pentassuglia L, Lim CC, Sawyer DB. Molecular and cellular mechanisms of anthracycline cardiotoxicity. Cardiovasc Toxicol 2007; 7:114-121.
4. Gewirtz DA. A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 1999; 57:727-741.
5. Thorn CF, Oshiro C, Marsh S, Hernandez-Boussard T, McLeod H, Klein TE, et al. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genomics 2011; 21:440-446.
6. Blasiak J, Gloc E, Wozniak K, Mlynarski W, Stolarska M, Skorski T, et al. Genotoxicity of idarubicin and its modulation by vitamins C and E and amifostine. Chem-Biol Interact 2002; 140:1-18.
7. Charak S, Mehrotra R. Structural investigation of idarubicin-DNA interaction: spectroscopic and molecular docking study. Int J Biol Macromol 2013; 60:213-218.
8. Aluko BT, Oloyede OI, Afolayan AJ. Polyphenolic contents and free radical scavenging potential of extracts from leaves of Ocimum americanum L. Pak J Biol Sci 2013; 16:22-30.
9. Majo DD, Giammanco M, Guardia ML, Tripoli E, Giammanco S, Finotti E. Flavanones in citrus fruit: structure–antioxidant activity relationships. Food Res Int 2005; 38:1161-1166.
10. Maurer HR. Bromelain: biochemistry, pharmacology and medical use. Cell Mol Life Sci 2001; 58:1234-1245.
11. Fouz N, Amid A, Hashim YZ. Cytokinetic study of MCF-7 cells treated with commercial and recombinant bromelain. Asian Pac J Cancer Prev 2014; 14:6709-6714.
12. Pillai K, Akhter J, Chua TC, Morris DL. Anticancer property of bromelain with therapeutic potential in malignant peritoneal mesothelioma. Cancer Invest 2013; 31:241-250.
13. Chobotova K, Vernallis AB, Majid FA. Bromelain’s activity and potential as an anti-cancer agent: Current evidence and perspectives. Cancer Lett 2010; 290:148-156.
14. Amini A, Masoumi-Moghaddam S, Ehteda A, Morris DL. Bromelain and N-acetylcysteine inhibit proliferation and survival of gastrointestinal cancer cells in vitro: significance of combination therapy. J Exp Clin Cancer Res 2014; 33:92-107.
15. Romano B, Fasolino I, Pagano E, Capasso R, Pace S, De Rosa G, et al. The chemopreventive action of bromelain, from pineapple stem (Ananas comosus L.), on colon carcinogenesis is related to antiproliferative and proapoptotic effects. Mol Nutr Food Res 2014; 58:457-465.
16. Majsterek I, Gloc E, Blasiak J, Reiter RJ. A comparison of the action of amifostine and melatonin on DNA-damaging effects and apoptosis induced by idarubicin in normal and cancer cells. J Pineal Res 2005; 38:254-263.
17. Wozniak K, Gloc E, Morawiec Z, Blasiak J. Amifostine can differentially modulate DNA double-strand breaks and apoptosis induced by idarubicin in normal and cancer cells. Exp Oncol 2008; 30:22-28.
18. Wysokinski D, Blasiak J, Wozniak K. Zinc differentially modulates DNA damage induced by anthracyclines in normal and cancer cells. Exp Oncol 2012; 34:327-331.
19. Ristic B, Bosnjak M, Arsikin K, Mircic A, Suzin-Zivkovic V, Bogdanovic A, et al. Idarubicin induces mTOR-dependent cytotoxic autophagy in leukemic cells. Exp Cell Res 2014; 326:90-102.
20. Kocyigit A, Koyuncu I, Taskin A, Dikilitas M, Bahadori F, Turkkan B. Antigenotoxic and antioxidant potentials of newly derivatized compound naringenin-oxime relative to naringenin on human mononuclear cells. Drug Chem Toxico 2016; 39:66-73.
21. Singh NP, Mccoy MT, Tice RR, Schneider EL. A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res 1988; 175:184-191.
22. Kocyigit A, Selek S, Celik H, Dikilitas M. Mononuclear leukocyte DNA damage and oxidative stress: the association with smoking of hand-rolled and filter-cigarettes. Mutat Res 2011; 721:136–141.
23. Aktepe N, Kocyigit A, Yukselten Y, Taskin A, Keskin C, Celik H. Increased DNA damage and oxidative stress among silver jewelry workers. Biol Trace Elem Res 2015; 164:185-191.
24. Liu K, Liu PC, Liu R, Wu X. Dual AO/EB staining to detect apoptosis in osteosarcoma cells compared with flow cytometry. Med Sci Monit Basic Res 2015; 21:15-20.
25. Gunes-Bayir A, Kocyigit A, Guler EM. In vitro effects of two major phenolic compounds from the family Lamiaceae plants on the human gastric carcinoma cells. Toxicol Ind Health 2018; 34:525-539.
26. Rahman A, Hussain A. Anticancer activity and apoptosis inducing effect of methanolic extract of Cordia dichotoma against human cancer cell line. Bangladesh J Pharmacol 2015; 10:27-34.
27. Raies AB, Bajic VB. In silico toxicology: computational methods for the prediction of chemical toxicity. Wiley Interdiscip Rev Comput Mol Sci 2016; 6:147-172.
28. Elmore S. Apoptosis: A Review of Programmed Cell Death. Toxicol Pathol 2007; 35:495-516.
29. Temkin SM, Fleming G. Current treatment of metastatic endometrial cancer. Cancer Control 2009; 16:38-45.
30. Yıldız C. The effect of Bevacizumab (VEGF monoclonal antibody) with or without classic chemotherapeutics in endometrium carcinoma cell culture. Medical Thesis. Turkey CoHE Thesis Center; 2010.
31. Ye Q, Zhang C, Wang Z, Feng Y, Zhou A, Xie S, et al. Induction of oxidative stress, apoptosis and DNA damage by koumine in Tetrahymena thermophila. PLoS One 2019; 14:212231-212246.
32. Sekhar SC, Venkatesh J, Cheriyan VT, Muthu M, Levi E, Assad H, et al. A H2AX⁻CARP-1 interaction regulates apoptosis signaling following DNA damage. Cancers 2019; 11:221-245.
33. Skipper A, Sims JN, Yedjou CG, Tchounwou PB. Cadmium chloride induces DNA damage and apoptosis of human liver carcinoma cells via oxidative stress. Int J Environ Res Public Health 2016; 13:88-98.
34. Li D, Huang Q, Lu M, Zhang L, Yang Z, Zong M, et al. The organophosphate insecticide chlorpyrifos confers its genotoxic effects by inducing DNA damage and cell apoptosis. Chemosphere 2015; 135:387-393.
35. Shalini S, Dorstyn L, Dawar S, Kumar S. Old, new and emerging functions of caspases. Cell Death Differ 2015; 22:526-539.
36. Qi SN, Yoshida A, Ueda T. Activation of caspases-3/7 is dispensable for idarubicin-induced apoptotic DNA fragmentation in human leukemia cells. Int J Oncol 2003; 22:1123-1128.
37. Kocyigit A, Guler EM, Karatas E, Caglar H, Bulut H. Dose-dependent proliferative and cytotoxic effects of melatonin on human epidermoid carcinoma and normal skin fibroblast cells. Mutat Res Genet Toxicol Environ Mutagen 2018; 829:50-60.