A new strategy of promoting cisplatin chemotherapeutic efficiency by targeting endoplasmic reticulum stress

Abstract

Abstract. Cisplatin (cis-diamminedichloroplatinum II, CDDP) is one of the most effective chemotherapeutic agents and is widely used in the treatment of solid tumors. However, its side effects and acquired resistance gained during the course of treatment may limit its usage. It is generally considered to be a cytotoxic drug that kills cancer cells by damaging their DNA and inhibiting DNA synthesis to induce apoptosis via the mitochondrial death pathway or through plasma membrane disruption, triggering the Fas death receptor pathway. The endoplasmic reticulum (ER) is one of the most important protein-folding compartments within the cell and an intracellular Ca 2+ storage organelle. The ER contains a number of molecular chaperones, which may play an important role in determining cellular sensitivity to ER stress and apoptosis. The aim of this review was to summarize our current understanding regarding the mechanisms of ER stress response by which cisplatin induces cell death and the basis for cisplatin resistance. Various aspects were addressed, including the two-way regulation of ER stress, the involvement of ER stress in cisplatin-induced cell death and drug resistance and the drugs enhancing cisplatin-induced cell death by interfering with ER stress. An understanding of how ER stress signaling pathways regulate cisplatin-induced cell death may enable the development of more effective therapeutic strategies for the treatment of cancer.

Phosphorylation of eIF2α suppresses cisplatin-induced p53 activation and apoptosis by attenuating oxidative stress via ATF4-mediated HO-1 expression in human renal proximal tubular cells

“…This suggests that regulation of p53 activity may be an important target for alleviating cisplatin nephrotoxicity. cisplatin nephrotoxicity is also associated with endoplasmic reticulum (ER) stress (16). Pre-activation of ER stress alleviates cisplatin-induced nephrotoxicity in various renal cell lines (17).…”

Calcium homeostasis in cisplatin resistant epithelial ovarian cancer

“…Cisplatin resistance may be associated with the altered regulation of multiple signaling pathways, including downregulation of apoptotic signals, and activation of pro-survival signals (Ali et al 2012;Gal-luzzi et al 2012;Davis et al 2014). Recent studies have shown that endoplasmic reticulum (ER) stress-associated apoptosis can be induced by cisplatin, and that ER stress tolerance may be involved in cisplatin resistance (Xu et al 2012(Xu et al , 2014(Xu et al , 2015a.…”

Cisplatin-induced regulation of signal transduction pathways and transcription factors in p53-mutated subclone variants of hepatoma cells: Potential application for therapeutic targeting

“…The ER is the most critical protein-folding compartment and an intracellular Ca 2+ storage organelle in cells (25). Thus, accumulating reactive nitrogen species could modify proteins and disrupt Ca 2+ homeostasis, which may trigger the induction of cisplatin-induced ER stress (26,27). Upon cisplatin treatment, intracellular NO levels increased nearly by 10-fold in the Mahlavu cells (Fig.…”

“…The present study revealed that cisplatin-induced ER stress response simultaneously provoked two prominent pathways that may induce cells apoptosis. The key effectors of ER stress-signaling pathways may modulate cisplatin-induced cell death (27) through GRP78 (24) or β-catenin (28). Therefore, identifying those molecules that can be used to predict cisplatin treatment response would enable therapy to be tailored on an individual HCC patient basis.…”

“…Since the upregulation of GRP78 was frequently observed in HCC cells (15), the present study investigated how cisplatin affects the expression of GRP78 in association with the possible nitrosative stress-mediated mechanism in the Mahlavu cell model. The uniqueness of the Mahlavu cells was that they constitutively overexpressed GRP78, likely through a mild, endogenously generated NO-mediated increase in the active p50 form of the transcription factor ATF6 (ATF6α-p50), which, by nuclear translocation, could release GRP78 from its conjugated form (18,26,27,31). In the present study, cisplatin was observed to suppress GRP78 through a mechanism involving the strong inhibition of the expression of ATF6α-p50.…”