ER Stress Response and Induction of Apoptosis in Malignant Pleural Mesothelioma: The Achilles Heel Targeted by the Anticancer Ruthenium Drug BOLD-100

Abstract

Malignant mesothelioma is a rare cancer arising from the serosal surfaces of the body, mainly from the pleural layer. This cancer is strongly related to asbestos exposure and shows a very inauspicious prognosis, because there are scarce therapeutic options for this rare disease. Thus, there is an urgent need to develop novel therapeutic approaches to treat this form of cancer. To explore the biology of malignant pleural mesothelioma (MPM), we previously observed that MPM cell lines show high expression of the GRP78 protein, which is a chaperone protein and the master regulator of the unfolded protein response (UPR) that resides in the endoplasmic reticulum (ER). Based on our previous studies showing the importance of GRP78 in MPM, we observed that BOLD-100, a specific modulator of GRP78 and the UPR, shows cytotoxicity against MPM cells. Our studies demonstrated that BOLD-100 increases ROS production and Ca2+ release from the ER, leading to ER stress activation and, ultimately, to cell death. Our in vitro data strongly suggest that BOLD-100 inhibits the growth of MPM cell lines, proposing the application as a single agent, or in combination with other standard-of-care drugs, to treat MPM.

Synthetic Small Molecule Modulators of Hsp70 and Hsp40 Chaperones as Promising Anticancer Agents

“…As far as drug repurposing is concerned, the disinfectant hexachlorophene ( 20 ) and the spasmolytic drug pinaverium bromide ( 4 ) are further interesting examples of Hsp70 inhibitory activity [ 50 , 82 ]. In contrast to the cationic mitochondria-targeting compounds with preference for mortalin binding, the anionic ruthenium complex 22 (KP1339) is an efficient Grp78 suppressor [ 85 , 86 , 87 , 88 ]. However, the exact anticancer mechanisms of action of such pleiotropic ruthenium complexes are only partially understood.…”

“…Grp78 is upregulated in asbestos-associated pleural mesothelioma, and, thus, the activity of 22 against this cancer was evaluated. Complex compound 22 was cytotoxic against mesothelioma cells (EC 50 = 71 µM for REN and 90 µM for MM98 cells), inhibited REN cell colony formation at a concentration of 100 µM, induced apoptosis in REN cells by activation of caspase-3/7 and caspase-8, increased ROS formation and cytosolic Ca 2+ levels, and suppressed Grp78 expression in REN cells [ 87 ]. CHOP and XPB1 expression were upregulated by compound 22 in REN cells.…”

Endoplasmic Reticulum Stress and Cancer: Could Unfolded Protein Response Be a Druggable Target for Cancer Therapy?

“…In malignant mesothelioma cell lines, treatment with BOLD-100 induce an increase in ROS production and Ca 2+ release from the ER, producing an activation leading to ER stress and, ultimately, to cell death [ 202 ].…”