Sabutoclax, pan-active BCL-2 protein family antagonist, overcomes drug resistance and eliminates cancer stem cells in breast cancer

Abstract

Misregulation of BCL-2 family of proteins renders a survival signal to withstand cytotoxic anticancer drugs and is often found in drug resistant cells. The drug resistance phenotype is also associated with an enhancement of cancer stem cell-like (CSC) characteristics. Thus, inhibition of anti-apoptotic BCL-2 family proteins has been proposed as a possible antineoplastic strategy, and BCL-2 inhibitors are currently being clinically trailed in patients with leukemia, lymphoma or non-small cell lung cancer. However, the effects of BCL-2 inhibitors on drug resistant breast cancer have not yet been elucidated. In the present study, the effect of sabutoclax, a pan-active BCL-2 protein family antagonist, on two chemoresistant breast cancer cell lines was assessed. We found that sabutoclax showed a significant cytotoxic activity on chemoresistant breast cancer cells both in vitro and in vivo. When chemotherapeutic agents were combined with sabutoclax, strong synergistic antiproliferative effects were observed. Sabutoclax induced the blockage of BCL-2, MCL-1, BCL-xL and BFL-1, which in turn led to caspase-3/7 and caspase-9 activation and modulation of Bax, Bim, PUMA and survivin expression. Furthermore, sabutoclax effectively eliminated the CSC subpopulation and reduced sphere formation of drug-resistant cells through down-regulation of the IL-6/STAT3 signaling pathway. A similar effect was observed in a small panel of nine breast tumors ex vivo. Our findings indicate that sabutoclax partially overcomes the drug resistance phenotype of breast cancer cells by reactivation of apoptosis, mediated by the inhibition of several anti-apoptotic BCL-2 family proteins, and eliminates CSCs by abolition of the IL-6/STAT3 pathway. This offers a strong rationale to explore the therapeutic strategy of using sabutoclax alone or in combination for chemotherapy-nonresponsive breast cancer patients.

Role of STAT3 signaling pathway in breast cancer

“…Furthermore, tagalide A and tagalol A are also found to inhibit the phosphorylation of STAT3 and JAK2 in breast cancer [86]. Additionally, sabutoclax, a pan-active BCL-2 protein family antagonist, is found to inhibit the IL-6/STAT3 pathway and thereby overcome multidrug resistance in breast cancer [85], whereas isoharringtonine (IHT) is found to suppress the STAT3/Nanong pathway to inhibit breast cancer proliferation [91].…”

MCL-1 plays an oncogenic role in breast cancer by modulating chemoresistance and stemness properties by activating Wnt/β-catenin

“…A recent study showed that targeting MCL-1 by either treatment an inhibitor or an siRNA sensitizes gastric, colorectal and pancreatic cancer cells [13,14]. For breast cancer, a variety of studies have shown that there is an identi ed relationship between MCL-1 and resistance [15,16]. However, interestingly, we found that MYC may cooperate with MCL-1 to maintain cancer stem cells (CSCs) [5].…”

Rottlerin ameliorates DSS-induced colitis by improving intestinal barrier function via activation of the Epac-2/Rap-1 signaling pathway

“…Bax is an important additional contributor affecting the balance of apoptosis [29,30] . We found that treatment with rottlerin increased the level of Bcl-2 in DSS-treated group and decreased the level of Bax.…”