Dihydroartemisinin Enhances the Therapeutic Efficacy of BH3 Mimetic Inhibitor in Acute Lymphoblastic Leukemia Cells Via Inhibition of Mcl-1

Overview

Journal Asian Pac J Cancer Prev

Specialty Oncology

Date 2024 Jan 29

PMID 38285800

Authors

Roya Nazmabadi

Marziyeh Pooladi

Jamal Amri

Yusef Abbasi

Hadi Karami

Marayam Darvish

Affiliations

Soon will be listed here.

Abstract

Introduction: Up-regulation of the anti-apoptotic proteins such as Mcl-1 is associated with the primary and secondary resistance of tumor cells to ABT-737 Bcl-2 inhibitor. The combined treatment of Bcl-2 inhibitors with Mcl-1 inhibitors has been proposed as an attractive therapeutic strategy to overcome this drug resistance. Here, we investigated the effect of dihydroartemisinin on Mcl-1 expression and sensitization of T-ALL cells to ABT-737.

Methods: The cell growth and survival were tested by the cell proliferation and MTT assays, respectively. The mRNA levels of Bcl-2, Mcl-1, Bax and P21 were examined by qRT-PCR. Apoptosis were detected by Hoechst 33342 staining and caspase-3 activity assay.

Results: Our data showed that combination treatment with dihydroartemisinin and ABT-737 caused a significant decrease in the IC50 value and synergistically reduced the cell survival compared with dihydroartemisinin or ABT-737 alone. ABT-737 enhanced the Mcl-1 mRNA expression. Dihydroartemisinin also down-regulated the expression of Bcl-2 and Mcl-1 and enhanced the P21 and Bax expression. Moreover, dihydroartemisinin enhanced the apoptosis induced by ABT-737 in MOLT-4 and MOLT-17 cell lines.

Conclusion: In conclusion, dihydroartemisinin demonstrates anti-tumor activities in human ALL cells via inhibition of cell survival and growth. Dihydroartemisinin augments the apoptotic effect of ABT-737 by inhibiting the expression of Mcl-1.

References

Handrick R, Ontikatze T, Bauer K, Freier F, Rubel A, Durig J . Dihydroartemisinin induces apoptosis by a Bak-dependent intrinsic pathway. Mol Cancer Ther. 2010; 9(9):2497-510. DOI: 10.1158/1535-7163.MCT-10-0051. View

Gaizo Moore V, Schlis K, Sallan S, Armstrong S, Letai A . BCL-2 dependence and ABT-737 sensitivity in acute lymphoblastic leukemia. Blood. 2007; 111(4):2300-9. PMC: 2234061. DOI: 10.1182/blood-2007-06-098012. View

Ashofteh N, Amini R, Molaee N, Karami H, Baazm M . MiRNA-Mediated Knock-Down of Bcl-2 and Mcl-1 Increases Fludarabine-Sensitivity in CLL-CII Cells. Asian Pac J Cancer Prev. 2021; 22(7):2191-2198. PMC: 8607086. DOI: 10.31557/APJCP.2021.22.7.2191. View

Gaizo Moore V, Brown J, Certo M, Love T, Novina C, Letai A . Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest. 2007; 117(1):112-21. PMC: 1716201. DOI: 10.1172/JCI28281. View

Baradaran B, Nazmabadi R, Ariyan Z, Sakhinia E, Karami H . Dual Targeting of Anti-Apoptotic Proteins Enhances Chemosensitivity of the Acute Myeloid Leukemia Cells. Asian Pac J Cancer Prev. 2022; 23(7):2523-2530. PMC: 9727342. DOI: 10.31557/APJCP.2022.23.7.2523. View

Gao N, Budhraja A, Cheng S, Liu E, Huang C, Chen J . Interruption of the MEK/ERK signaling cascade promotes dihydroartemisinin-induced apoptosis in vitro and in vivo. Apoptosis. 2011; 16(5):511-23. DOI: 10.1007/s10495-011-0580-6. View

Hou J, Wang D, Zhang R, Wang H . Experimental therapy of hepatoma with artemisinin and its derivatives: in vitro and in vivo activity, chemosensitization, and mechanisms of action. Clin Cancer Res. 2008; 14(17):5519-30. DOI: 10.1158/1078-0432.CCR-08-0197. View

Alamdari-Palangi V, Karami Z, Karami H, Baazm M . MiRNA-7 Replacement Effect on Proliferation and Tarceva-Sensitivity in U373-MG Cell Line. Asian Pac J Cancer Prev. 2020; 21(6):1747-1753. PMC: 7568905. DOI: 10.31557/APJCP.2020.21.6.1747. View

Sanchez V, Nichols C, Kim H, Gang E, Kim Y . Targeting PI3K Signaling in Acute Lymphoblastic Leukemia. Int J Mol Sci. 2019; 20(2). PMC: 6358886. DOI: 10.3390/ijms20020412. View

10.

Preuss E, Hugle M, Reimann R, Schlecht M, Fulda S . Pan-mammalian target of rapamycin (mTOR) inhibitor AZD8055 primes rhabdomyosarcoma cells for ABT-737-induced apoptosis by down-regulating Mcl-1 protein. J Biol Chem. 2013; 288(49):35287-96. PMC: 3853277. DOI: 10.1074/jbc.M113.495986. View

11.

Efferth T . Mechanistic perspectives for 1,2,4-trioxanes in anti-cancer therapy. Drug Resist Updat. 2005; 8(1-2):85-97. DOI: 10.1016/j.drup.2005.04.003. View

12.

Li P, Yang S, Dou M, Chen Y, Zhang J, Zhao X . Synergic effects of artemisinin and resveratrol in cancer cells. J Cancer Res Clin Oncol. 2014; 140(12):2065-75. DOI: 10.1007/s00432-014-1771-7. View

13.

Shahverdi M, Amri J, Karami H, Baazm M . Knockdown of Myeloid Cell Leukemia-1 by MicroRNA-101 Increases Sensitivity of A549 Lung Cancer Cells to Etoposide. Iran J Med Sci. 2021; 46(4):298-307. PMC: 8288490. DOI: 10.30476/ijms.2020.83173.1203. View

14.

Efferth T . From ancient herb to modern drug: Artemisia annua and artemisinin for cancer therapy. Semin Cancer Biol. 2017; 46:65-83. DOI: 10.1016/j.semcancer.2017.02.009. View

15.

Tahir S, Yang X, Anderson M, Morgan-Lappe S, Sarthy A, Chen J . Influence of Bcl-2 family members on the cellular response of small-cell lung cancer cell lines to ABT-737. Cancer Res. 2007; 67(3):1176-83. DOI: 10.1158/0008-5472.CAN-06-2203. View

16.

Follini E, Marchesini M, Roti G . Strategies to Overcome Resistance Mechanisms in T-Cell Acute Lymphoblastic Leukemia. Int J Mol Sci. 2019; 20(12). PMC: 6627878. DOI: 10.3390/ijms20123021. View

17.

Faderl S, OBrien S, Pui C, Stock W, Wetzler M, Hoelzer D . Adult acute lymphoblastic leukemia: concepts and strategies. Cancer. 2010; 116(5):1165-76. PMC: 5345568. DOI: 10.1002/cncr.24862. View

18.

Qin G, Zhao C, Zhang L, Liu H, Quan Y, Chai L . Dihydroartemisinin induces apoptosis preferentially via a Bim-mediated intrinsic pathway in hepatocarcinoma cells. Apoptosis. 2015; 20(8):1072-86. DOI: 10.1007/s10495-015-1132-2. View

19.

Hargraves K, He L, Firestone G . Phytochemical regulation of the tumor suppressive microRNA, miR-34a, by p53-dependent and independent responses in human breast cancer cells. Mol Carcinog. 2015; 55(5):486-98. PMC: 4905729. DOI: 10.1002/mc.22296. View

20.

Amri J, Molaee N, Karami H, Baazm M . Combination of two miRNAs has a stronger effect on stimulating apoptosis, inhibiting cell growth, and increasing erlotinib sensitivity relative to single miRNA in A549 lung cancer cells. Biotechnol Appl Biochem. 2021; 69(4):1383-1394. DOI: 10.1002/bab.2211. View