Work

Discovery and optimization of cardenolides inhibiting HSF1 activation in human colon HCT-116 cancer cells

Year: 2018

Type: article

Abstract: // Alina D. Nikotina 1 , Lidia Koludarova 1 , Elena Y. Komarova 1 , Elena R. Mikhaylova 1 , Nikolay D. Aksenov 1 , Roman Suezov 1, 3 , Viktor G. Kartzev 2 , Boris A. Margulis 1 and Irina V. Guzhova 1 1 Laboratory of Cell Protection Mechanisms, Institute of Cytology of Russian Academy of Sciences, St. Petersburg 194064, Russia 2 InterBioscreen, Chernogolovka 142432, Russia 3 Saint Petersburg Technical University, St. Petersburg 190013, Russia Correspondence to: Irina V. Guzhova, email: [email protected] Keywords: heat shock factor 1 (HSF1); Hsp70; anticancer drugs; combined antitumor therapy Received: February 19, 2018 Accepted: May 19, 2018 Published: June 05, 2018 ABSTRACT Combinational anticancer therapy demonstrates increased efficiency, as it targets different cell-survival mechanisms and allows the decrease of drug dosages that are often toxic to normal cells. Inhibitors of the heat shock response (HSR) are known to reduce the efficiency of proteostasis mechanisms in many cancerous cells, and therefore, may be employed as anti-tumor drug complements. However, the application of HSR inhibitors is limited by their cytotoxicity, and we suggested that milder inhibitors may be employed to sensitize cancer cells to a certain drug. We used a heat-shock element-luciferase reporter system and discovered a compound, CL-43, that inhibited the levels of heat shock proteins 40, 70 (Hsp70), and 90 kDa in HCT-116 cells and was not toxic for cells of several lines, including normal human fibroblasts. Consequently, CL-43 was found to reduce colony formation and motility of HCT-116 in the appropriate assays suggesting its possible application in the exploration of biology of metastasizing tumors. Importantly, CL-43 elevated the growth-inhibitory and cytotoxic activity of etoposide, cisplatin, and doxorubicin suggesting that the pro-drug has broad prospect for application in a variety of anti-tumor therapy schedules.

Source: Oncotarget

DOI: 10.18632/oncotarget.25545