Nelfinavir induces mitochondria protection by ERK1/2-mediated mcl-1 stabilization that can be overcome by sorafenib

Abstract

The HIV protease inhibitor nelfinavir is an investigational drug for cancer treatment. We have previously demonstrated induction of apoptosis by nelfinavir even in chemo-resistant ovarian cancer cells. In contrast to the pro-apoptotic effect of nelfinavir on human cancer cells, we noticed a significant upregulation of the anti-apoptotic mitochondrial membrane protein mcl-1 by nelfinavir, resulting in a mitochondria-independent induction of apoptosis. Upregulation of mcl-1 was associated with enhanced phosphorylation of both mcl-1 and of ERK1/2 (extracellular signal-regulated kinases 1/2). ERK1/2 enhanced stability of mcl-1 protein expression by serine-163 phosphorylation. The combination of nelfinavir with sorafenib, a clinically applied inhibitor of the RAS/RAF/ ERK1/2 pathway, inhibited nelfinavir-induced ERK1/2 activation and mcl-1 protein upregulation. Further, the combination of nelfinavir with sorafenib induced mitochondrial membrane potential disruption and resulted in an improved activity of nelfinavir on ovarian cancer cells. Thus, a combination of these two investigational anticancer drugs could be of interest especially because of their unique mechanism of apoptosis induction even in otherwise chemo-resistant human cancer cells.

Tamoxifen enhances the cytotoxic effects of nelfinavir in breast cancer cells

“…Some previous studies have indicated the inhibition of proteasomal activity by HIV protease inhibitors, including nelfinavir [26,28]. The fact that nelfinavir has no influence on expression of the proteasome-regulated NF-κB inhibitor IκB (Figure 4), however, indirectly suggests that nelfinavir has no effect on the proteasomal activity of breast cancer cells.…”

“…We have previously described an upregulation of the anti-apoptotic mcl-1 protein by nelfinavir in ovarian cancer cells [26], but this could only be observed in one (MDA-MB-435) of the four tested breast cancer cell lines. Nelfinavir has further been described as reducing AKT phosphorylation, resulting in enhanced radiosensitivity [11,16] - which could be of special importance for breast cancer treatment, for which radiotherapy can be applied.…”

“…In contrast, nelfinavir markedly enhanced AKT phosphorylation in some breast cancer cell lines (MDA-MB-453 cells and MDA-MB-435 cells). This observation is not surprising, however, since we previously demonstrated activation of the cell-protective ERK1/2 signalling pathway by nelfinavir [26]. The endoplasmic stress reaction is primarily a cell-protective mechanism, aiming to rescue cells from transient stress-induced cell damage [21,33].…”

“…Still, the prospects of nelfinavir as an anti-cancer drug will rely less on its efficacy as a single drug and more on its ability to cooperate with or sensitise to other chemotherapeutic drugs or cancer treatment options. For example, we have recently demonstrated that nelfinavir cooperates with the multiple kinase inhibitor sorafenib to induce apoptosis in various cancer cell types [26,29], and enhances TNF-related apoptosis inducing ligand sensitivity in ovarian cancer cells [30]. …”

Complete response after sorafenib therapy for hepatocellular carcinoma in an HIV-HBV co infected patient: Possible synergy with HAART ? A case report

“…The PI3/Akt/mTOR pathway plays a critical role in HCC [16] and combined inhibition of that pathway plus RAF and/or angiogenesis inhibition that is mediated by sorafenib, could act synergistically in blocking the cell growth of tumor cells [17]. Furthermore, the in vitro combination of the HIV protease inhibitor nelfinavir, with sorafenib resulted in induction of apoptosis in ovarian cancer and leukemia cell lines suggesting a possible synergistic effect of also that combination [18,19].…”