Downregulation of Bcl-x L and Mcl-1 is sufficient to induce cell death in mesothelioma cells highly refractory to conventional chemotherapy

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis and limited response to platinum-based chemotherapy. Several lines of evidence support a role for the anti-apoptotic protein Bcl-x(L) in MPM chemoresistance. Since it has been recently suggested that Mcl-1 cooperates with Bcl-x(L) for protection against cell death, we investigated the response of mesothelioma cell lines to the downregulation of Bcl-x(L) (alone or in combination with cisplatin) and the potential interest of its concomitant inhibition with that of Mcl-1. Using RNA interference, we showed that Bcl-x(L) depletion sensitized two highly chemoresistant mesothelioma cell lines to cisplatin and that under this treatment, one cell line, MSTO-211H, displayed an apoptotic type of cell death, whereas the other, NCI-H28, evidenced mainly necrotic-type cell death. Otherwise, the inhibition of Mcl-1 by cisplatin may contribute to this induction of cell death observed after Bcl-x(L) downregulation. Strikingly, we observed that the simultaneous inhibition of Bcl-x(L) and Mcl-1 using small interfering RNA (siRNA) induced a massive cell death in the absence of chemotherapy and was sufficient to avoid escape to treatment in MSTO-211H cells. In NCI-H28, the addition of a low cisplatin concentration allowed to impede the long-term recovery observed after treatment by the siRNA combination. Together, these findings provide a strong molecular basis for the clinical evaluation of therapies targeting both Bcl-x(L) and Mcl-1, alone or in combination with conventional chemotherapy, for the treatment of MPM.

Why Anti-Energetic Agents Such as Citrate or 3-Bromopyruvate Should be Tested as Anti-Cancer Agents: Experimental In Vitro and In Vivo Studies

“…-in MSTO-211H cells, we observed that citrate induced an early diminution of the expression of the anti-apoptotic protein Mcl-1 (Fig. 3 c), which is a protein member of the Bcl-2 family playing a key role, with Bcl-x L , in the chemoresistance of malignant cancers, especially of mesothelioma, as we showed (Varin, 2010). Indeed, concomitant inhibition of these two anti-apoptotic proteins by specific siRNA (directed against Mcl-1 or Bcl-x L ) caused complete cell death of MSTO-211H cells, whereas inhibition of only one of these two anti-apoptotic molecules, even combined with cisplatin at a low dose (5 g per ml), was not sufficient to eradicate cultured cells (34).…”

“…Therefore, we wondered if they were able to undergo apoptosis? We showed they could, if they were treated by two specific siRNA directed against Mcl-1 or Bcl-x L associated with a low dose of cisplatin (5g per ml) (Varin, 2010). A: This experiment showed the efficacy of the association of a cisplatin injection at 21, followed by a series of 4 intra-peritoneal injections of 3-BrPA.…”

“…Our works have resulted in several publications (Lu, 2011;Varin, 2010;Zhang, 2006Zhang, , 2009aZhang, , 2009b):…”

Inhibition of STAT3 Signaling Pathway by Nitidine Chloride Suppressed the Angiogenesis and Growth of Human Gastric Cancer

“…Therefore, suppression of Bcl-2 and Bcl-xL expression may be a useful strategy to potentiate cancer apoptosis (49,50). Notably, we found that STAT3-dependent target genes including Bcl-2 and Bcl-xL were dose-dependently downregulated by nitidine chloride.…”

The anti-apoptotic members of the Bcl-2 family are attractive tumor-associated antigens

“…In this regard, Tanaka et al described that the co-expression of different apoptosis regulators in breast carcinoma was strongly associated with reduced apoptotic index (AI) and poor overall survival [46]. A similar association has been described in other cancers [47][48][49]. Thus, in most human cancers, inhibition of apoptosis is a general feature, and expression of anti-apoptosis genes, e.g.…”