Targeting HDAC enzymes by SAHA enhances the cytotoxic effects of cisplatin on acute myeloid leukemia cells

Yıl 2024, Cilt: 41 Sayı: 3, 524 - 529, 30.09.2024

Merve Şansaçar , Özge Pekin , Emel Başak Gencer Akcok

Öz

Chemotherapy is a widely used therapeutic approach to combat hematopoietic malignancies such as acute myeloid leukemia (AML). Although cisplatin is known as the first-generation platinum-based chemotherapy inhibitor, the wide use of cisplatin eventually leads to drug resistance, which is the biggest impediment to cancer chemotherapy. Histone deacetylase enzyme (HDAC) inhibitors have the ability to induce cell cycle arrest and apoptosis in different types of cancer, which stands as a promising alternative for those cancer patients not appropriate for intensive chemotherapy. This study concluded that there was a significant decrease in the proliferation of MOLM-13 and MV4-11 FLT3-ITD+ AML cell lines with the increasing SAHA and cisplatin concentrations in 48 hours using MTT cell proliferation assay. Moreover, the combination of SAHA and cisplatin led to a reduction in the proliferation of both cell lines correlated with the synergistic effect of the two drugs depending on the combination index (CI). Furthermore, investigating apoptosis for combined administration resulted in increased induction of apoptosis by Annexin-V/PI double staining. In conclusion, although additional studies are needed to fully elucidate the molecular mechanism underlying this combination, we propose a new approach to targeting AML, as AML increases over time with drug resistance and the consequent year-on-year increase in patient mortality.

Anahtar Kelimeler

histone deacetylase inhibitors, cisplatin, acute myeloid leukemia, combination treatment, apoptosis

Kaynakça

• Rubnitz JE, Gibson B, Smith FO. Acute Myeloid Leukemia. Pediatr Clin North Am. 2008;55(1):21–51.
• Prada-Arismendy J, Arroyave JC, Röthlisberger S. Molecular biomarkers in acute myeloid leukemia. Blood Rev. 2017;31(1):63–76.
• Brown E, Guinn B ann. Molecular Mechanisms and Therapies of Myeloid Leukaemia. Int J Mol Sci. 2022;23(11):6251.
• Carter JL, Hege K, Yang J, Kalpage HA, Su Y, Edwards H, et al. Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy. Signal Transduct Target Ther. 2020 Dec 18;5(1):288.
• Zhang J, Gao X, Yu L. Roles of Histone Deacetylases in Acute Myeloid Leukemia With Fusion Proteins. Front Oncol. 2021;11:741746.
• Liu P, Yang F, Zhang L, Hu Y, Chen B, Wang J, et al. Emerging role of different DNA methyltransferases in the pathogenesis of cancer. Front Pharmacol. 2022;13:958146.
• San José-Enériz, Gimenez-Camino, Agirre, Prosper. HDAC Inhibitors in Acute Myeloid Leukemia. Cancers (Basel). 2019;11(11):1794.
• Quintás-Cardama A, Santos FPS, Garcia-Manero G. Histone deacetylase inhibitors for the treatment of myelodysplastic syndrome and acute myeloid leukemia. Leukemia. 2011;25(2):226–35.
• San José-Enériz, Gimenez-Camino, Agirre, Prosper. HDAC Inhibitors in Acute Myeloid Leukemia. Cancers (Basel). 2019;11(11):1794.
• Li Y, Seto E. HDACs and HDAC Inhibitors in Cancer Development and Therapy. Cold Spring Harb Perspect Med. 2016;6(10):a026831.
• Ungerstedt JS, Sowa Y, Xu WS, Shao Y, Dokmanovic M, Perez G, et al. Role of thioredoxin in the response of normal and transformed cells to histone deacetylase inhibitors. Proc Natl Acad Sci U S A. 2005;102(3):673-8.
• Konsoula Z, Velena A, Lee R, Dritschilo A, Jung M. Histone Deacetylase Inhibitor: Antineoplastic Agent and Radiation Modulator. Adv Exp Med Biol. 2011;720:171-9..
• Siddik ZH. Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene. 2003;22(47):7265–79.
• Suraweera A, O'Byrne KJ, Richard DJ. Combination Therapy With Histone Deacetylase Inhibitors (HDACi) for the Treatment of Cancer: Achieving the Full Therapeutic Potential of HDACi. Front Oncol. 2018;8:92.
• Şansaçar M, Sağır H, Gencer Akçok EB. Inhibition of PI3K-AKT-mTOR pathway and modulation of histone deacetylase enzymes reduce the growth of acute myeloid leukemia cells. Med Oncol. 2023;41(1):31.
• 1Ghosh S. Cisplatin: The first metal based anticancer drug. Bioorg Chem. 2019;88:102925.
• Lugones Y, Loren P, Salazar LA. Cisplatin Resistance: Genetic and Epigenetic Factors Involved. Biomolecules. 2022;12(10):1365.
• Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O, et al. Molecular mechanisms of cisplatin resistance. Oncogene. 2012;31(15):1869–83.
• Minerva, Bhat A, Verma S, Chander G, Jamwal RS, Sharma B, et al. Cisplatin-based combination therapy for cancer. J Cancer Res Ther. 2023;19(3):530–6.
• Dasari S, Njiki S, Mbemi A, Yedjou CG, Tchounwou PB. Pharmacological Effects of Cisplatin Combination with Natural Products in Cancer Chemotherapy. Int J Mol Sci. 2022;23(3):1532.
• Long J, Jia MY, Fang WY, Chen XJ, Mu LL, Wang ZY, et al. FLT3 inhibition upregulates HDAC8 via FOXO to inactivate p53 and promote maintenance of FLT3-ITD+ acute myeloid leukemia. Blood. 2020;135(17):1472–83.
• Skopek R, Palusińska M, Kaczor-Keller K, Pingwara R, Papierniak-Wyglądała A, Schenk T, et al. Choosing the Right Cell Line for Acute Myeloid Leukemia (AML) Research. Int J Mol Sci. 2023;24(6):5377.
• Ma X, Zhao M, Wu ZX, Yao J, Zhang L, Wang J, et al. The Histone Deacetylase Inhibitor I13 Induces Differentiation of M2, M3 and M5 Subtypes of Acute Myeloid Leukemia Cells and Leukemic Stem-Like Cells. Front Oncol. 2022;12:855570.
• Yao J, Li G, Cui Z, Chen P, Wang J, Hu Z, et al. The Histone Deacetylase Inhibitor I1 Induces Differentiation of Acute Leukemia Cells With MLL Gene Rearrangements via Epigenetic Modification. Front Pharmacol. 2022;13:876076.
• Zhang Y, Wang L, Zi Y, Zhang L, Guo Y, Huang Y. Oridonin effectively reverses the drug resistance of cisplatin involving induction of cell apoptosis and inhibition of MMP expression in human acute myeloid leukemia cells. Saudi J Biol Sci. 2017;24(3):678–86.
• Kyaw MTH, Yamaguchi Y, Choijookhuu N, Yano K, Takagi H, Takahashi N, et al. The HDAC Inhibitor, SAHA, Combined with Cisplatin Synergistically Induces Apoptosis in Alpha-fetoprotein-producing Hepatoid Adenocarcinoma Cells. Acta Histochem Cytochem. 2019;52(1):1–8.
• Jin KL, Park JY, Noh EJ, Hoe KL, Lee JH, Kim JH, et al. The effect of combined treatment with cisplatin and histone deacetylase inhibitors on HeLa cells. J Gynecol Oncol. 2010;21(4):262.
• Shen J, Huang C, Jiang L, Gao F, Wang Z, Zhang Y, et al. Enhancement of cisplatin induced apoptosis by suberoylanilide hydroxamic acid in human oral squamous cell carcinoma cell lines. Biochem Pharmacol. 2007;73(12):1901–9.
• Hou M, Huang Z, Chen S, Wang H, Feng T, Yan S, et al. Synergistic antitumor effect of suberoylanilide hydroxamic acid and cisplatin in osteosarcoma cells. Oncol Lett. 2018;16(4):4663-4670;
• Kumar B, Yadav A, Lang JC, Teknos TN, Kumar P. Suberoylanilide hydroxamic acid (SAHA) reverses chemoresistance in head and neck cancer cells by targeting cancer stem cells via the downregulation of nanog. Genes Cancer. 2015;6(3–4):169–81.