Co-inhibition of BCL-XL and MCL-1 with selective BCL-2 family inhibitors enhances cytotoxicity of cervical cancer cell lines

Siti Fairus Abdul Rahman; Kalaivani Muniandy; Yong Kit Soo; Elvin Yu Huai Tiew; Ke Xin Tan; Timothy E Bates; Nethia Mohana-Kumaran

doi:10.1016/j.bbrep.2020.100756

Co-inhibition of BCL-XL and MCL-1 with selective BCL-2 family inhibitors enhances cytotoxicity of cervical cancer cell lines

Biochem Biophys Rep. 2020 Apr 22:22:100756. doi: 10.1016/j.bbrep.2020.100756. eCollection 2020 Jul.

Authors

Siti Fairus Abdul Rahman¹, Kalaivani Muniandy², Yong Kit Soo¹, Elvin Yu Huai Tiew¹, Ke Xin Tan¹, Timothy E Bates³, Nethia Mohana-Kumaran¹

Affiliations

¹ School of Biological Sciences, Universiti Sains Malaysia, 11800, Penang, Malaysia.
² Institute for Molecular Medicine, Universiti Sains Malaysia, 11800, Penang, Malaysia.
³ Drugs with A Difference Limited, 6 Science and Technology Park, University Boulevard, Nottingham, NG6 2RF, United Kingdom.

Abstract

Development of resistance to chemo- and radiotherapy in patients suffering from advanced cervical cancer narrows the therapeutic window for conventional therapies. Previously we reported that a combination of the selective BCL-2 family inhibitors ABT-263 and A-1210477 decreased cell proliferation in C33A, SiHa and CaSki human cervical cancer cell lines. As ABT-263 binds to both BCL-2 and BCL-XL with high affinity, it was unclear whether the synergism of the drug combination was driven either by singly inhibiting BCL-2 or BCL-XL, or inhibition of both. In this present study, we used the BCL-2 selective inhibitor ABT-199 and the BCL-XL selective inhibitor A1331852 to resolve the individual antitumor activities of ABT-263 into BCL-2 and BCL-XL dependent mechanisms. A-1210477 was substituted for the orally bioavailable S63845. Four cervical cancer cell lines were treated with the selective BCL-2 family inhibitors ABT-199, A1331852 and S63845 alone and in combination using 2-dimensional (2D) and 3-dimensional (3D) cell culture models. The SiHa, C33A and CaSki cell lines were resistant to single agent treatment of all three drugs, suggesting that none of the BCL-2 family of proteins mediate survival of the cells in isolation. HeLa cells were resistant to single agent treatment of ABT-199 and A1331852 but were sensitive to S63845 indicating that they depend on MCL-1 for survival. Co-inhibition of BCL-2 and MCL-1 with ABT-199 and S63845, inhibited cell proliferation of all cancer cell lines, except SiHa. However, the effect of the combination was not as pronounced as combination of A1331852 and S63845. Co-inhibition of BCL-XL and MCL-1 with A1331852 and S63845 significantly inhibited cell proliferation of all four cell lines. Similar data were obtained with 3-dimensional spheroid cell culture models generated from two cervical cancer cell lines in vitro. Treatment with a combination of A1331852 and S63845 resulted in inhibition of growth and invasion of the 3D spheroids. Collectively, our data demonstrate that the combination of MCL-1-selective inhibitors with either selective inhibitors of either BCL-XL or BCL-2 may be potentially useful as treatment strategies for the management of cervical cancer.

Keywords: A1331852; ABT-199; Apoptosis; Cervical cancer; S63845; Selective BCL-2 inhibitors.