ABT-737 synergizes with Bortezomib to kill melanoma cells

Abstract

SummaryThe BH3 mimetic ABT-737 is a potent inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-XL, and Bcl-w. The Bcl-2 family modulates sensitivity to anticancer drugs in many cancers, including melanomas. In this study, we examined whether ABT-737 is effective in killing melanoma cells either alone or in combination with a proteasome inhibitor already in clinical use (Bortezomib) in vitro and in vivo, and further evaluated the mechanisms of action. Results showed that ABT-737 alone induced modest cytotoxicity in melanoma cells, but only at higher doses. Knock-down of the anti-apoptotic proteins Bcl-2, Bcl-XL, or Mcl-1 with siRNAs demonstrated that Mcl-1 is the critical mediator of melanoma's resistance to ABT-737 treatment. However, ABT-737 displayed strong synergistic lethality when combined with Bortezomib. Immunoblot analyses demonstrated that Bortezomib increased expression of Noxa, a pro-apoptotic Bcl-2 member that antagonizes Mcl-1. Additionally, siRNA-mediated inhibition of Noxa expression protected melanoma cells from cytotoxicity induced by the combination treatment. These results demonstrate that Bortezomib synergizes with ABT-737 by neutralizing Mcl-1's function via increased levels of Noxa. In a xenograft mouse model, although drug doses were limited due to toxicity, ABT-737 or Bortezomib slowed melanoma tumor growth compared to the control, and the drug combination significantly decreased growth compared to either drug alone. These data imply that less toxic drugs fulfilling a function similar to Bortezomib to neutralize Mcl-1 are promising candidates for combination with ABT-737 for treating melanomas.

Selective targeting of antiapoptotic BCL‐2 proteins in cancer

“…ABT‐737 exerted single‐agent activity in small cell lung cancer (SCLC) and lymphoma cells and in vitro tumor models. Other laboratories and we thoroughly studied the effects of ABT‐737 on multiple solid and hematological malignancies as single agent or in combination with chemotherapy, radiotherapy, and targeted therapies . The poor oral availability of ABT‐737 led to the development of its orally available analog, ABT‐263 (navitoclax), which paved the way for clinical trials of the first generation of BCL‐2/BCL‐XL inhibitors (Table ).…”

Inhibition of proteasome deubiquitinase activity: a strategy to overcome resistance to conventional proteasome inhibitors?

“…Both Bcl-2 and Bcl-X L function to dampen the apoptotic response by hindering Bax-Bak mediated perforation of the mitochondrial outer membrane, thus preventing cytochrome-c release and activation of the caspase cascade. Several groups have reported that the anti-tumour effect of bortezomib is greatly enhanced by antagonists of Bcl-2 function (Johnson-Farley et al, 2015;Kunami et al, 2014;Paoluzzi et al, 2008;Reuland et al, 2012). The Bcl-2 inhibitors ABT-737 and ABT-199 respectively enhance the cytotoxicity of bortezomib in adult T-cell leukaemia/lymphoma (Kunami et al, 2014) and "double hit" lymphoma cells (Johnson-Farley et al, 2015).…”

Therapeutic interventions to disrupt the protein synthetic machinery in melanoma

“…Bortezomib is FDA approved for the treatment of multiple myeloma and mantle cell lymphoma and is a potential treatment option for metastatic melanoma (Shahshahan et al., ). It is being tested in combination with other agents such as ABT‐737, sorafenib, and dacarbazine for better efficacy killing melanoma cells (Kumar et al., ; Poklepovic et al., ; Reuland et al., ). Thus, the therapeutic activation of HRI, like PERK and PKR activation, is a promising option to therapeutically inhibit melanoma development.…”