ABT-737 potentiates cisplatin-induced apoptosis in human osteosarcoma cells via the mitochondrial apoptotic pathway

Abstract

ABT-737 is a BH-3 mimetic that inhibits Bcl-2 and induces apoptosis of cancer cells, which has potential for anticancer therapies. Studies have shown that Bcl-2 expression in human osteosarcoma (OS) cells plays a significant role in tumor progression; however, its effects on OS cell apoptosis are still unknown. Therefore, we examined whether ABT-737 was effective in eliminating human U-2OS cells, either alone or in combination with the chemotherapy drug cisplatin [cis-diamminedichloroplatinum (II); DDP]. Furthermore, we studied the molecular mechanisms of ABT-737 in combination with DDP to induce apoptosis. To analyze the role of ABT-737 and/or DDP on osteosarcoma progression, CCK-8 viability assay, flow cytometry, Hoechst 33258 staining, and western blots were performed. Combined use of ABT-737 and DDP synergistically suppressed cell viability and induced apoptosis in human U-2OS cells when compared with either compound treated alone at low doses. We found that the combination of ABT-737 and DDP upregulated the expression of the pro-apoptotic protein Bax and downregulated the expression of the pro-survival protein Bcl-2, resulting in a change in the Bax/Bcl-2 ratio, release of cytochrome c, and activation of the mitochondrial apoptotic pathway, which resulted in caspase-9 and caspase-3 activation and PARP cleavage. Our results demonstrated that ABT-737 alone has a nominal influence on human U-2OS cells when treated within the clinically administered range, but when combined with DDP, it can inhibit the proliferation of human U-2OS cells by inducing apoptosis via the mitochondrial apoptotic pathway.

Suppression of YAP by DDP disrupts colon tumor progression

“…In 1972, it became the first metal-based drug to enter clinical trials and was initially applied in a clinical setting in 1979 ( 19 ). DDP is now a gold standard drug used for the treatment of testicular cancer (for which it has a 90% cure rate) and also for the treatment of head and neck, cervical, breast, lung, ovarian, gastric and bladder cancers, among many others ( 20 , 21 ). DDP exerts its antitumor activity through its alkylating properties.…”

“…These adducts cause the DNA helix to bend by up to 60% towards the major groove and unwind, inhibiting further DNA replication and transcription. This ultimately leads to cell death ( 21 , 26 , 27 ). However, the continuing clinical success of DDP is hindered by two major limitations, the development of DDP-resistant cancer cells and the toxic side-effects of the drug.…”

Daidzein induces choriocarcinoma cell apoptosis in a dose-dependent manner via the mitochondrial apoptotic pathway

“…In the intrinsic pathway, mitochondria serve a role in response to internal stimuli that result in an increase in mitochondrial outer membrane permeability (MOMP) (15). Alterations in MOMP lead to release of proteins from inside the mitochondria to the cytoplasm, and these proteins activate the caspase cascade (typically caspase-9) and other apoptotic responses, including the cleavage of poly(ADP-ribose) polymerase (PARP)-1 (16,17). MOMP is primarily controlled by anti-apoptotic proteins, including apoptosis regulator B cell lymphoma (Bcl)-2, Bcl-2-like protein 1, induced myeloid leukemia cell differentiation protein-1, Bcl-2-related protein A1, Bcl-2-like protein 10 and Bcl-2-like protein 2, and pro-apoptotic proteins, including Bcl-2 associated X, apoptosis regulator (Bax), Bcl-2 homologous antagonist/killer, BH3-interacting domain death agonist, Bcl-2-like protein 11 and Bcl-2-associated agonist of cell death (18).…”

Chemoresistance-Related Stem Cell Signaling in Osteosarcoma and Its Plausible Contribution to Poor Therapeutic Response: A Discussion That Still Matters

“…In this regard, attempts have been made to inhibit the relevant anti-apoptotic proteins, namely, Bcl-2, Bcl-xL and Bcl-W, using the BH-3 mimetic ABT-737 [ 184 , 185 , 186 ]. These preliminary data provide a rationale for a wider exploratory use of inhibitors of anti-apoptotic proteins to target chemoresistance of tumor cells in osteosarcoma, as earlier suggested [ 187 , 188 , 189 ], as well as CSCs as previously endeavored in other tumor types [ 184 , 185 , 186 , 190 ].…”