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

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.

Etoposide-Induced Apoptosis in Cancer Cells Can Be Reinforced by an Uncoupled Link between Hsp70 and Caspase-3

“…Our results revealed that pretreatment with BT44 reduced the resistance of colon carcinoma cells to etoposide ( Figure 3 ) and increased etoposide-induced apoptosis in U-937 cells with high levels of Hsp70 (U-937 wt HS and U-937 hsp70 ; Figure 4 B,C). Similar growth inhibition and pro-apoptotic effects have been demonstrated in HCT-116 cell lines following modulation of the activity of the HSF1 molecular chaperone [ 24 ].…”

Radiosensitization of HSF-1 Knockdown Lung Cancer Cells by Low Concentrations of Hsp90 Inhibitor NVP-AUY922

“…With respect to future clinical applications of a combined HSF-1 and Hsp90 inhibition to overcome radioresistance of tumor cells, presently different HSF-1 inhibiting substances such as quercetin [65], KNK437 [66], triptolide [67], NZ28 [29,31], N-amino-ethylamino derivative of colchicine (AEAC) [68], and cardenolide [69] are under investigations. However, effective concentrations in the micromolar range of quercetin, KNK437 and NZ28 are expected to exert adverse effects in patients.…”

Heat Shock Factor 1 as a Prognostic and Diagnostic Biomarker of Gastric Cancer

“…Although not yet identified in gastric cancer, many HSF1 mediated inhibitors are being studied. Cantharidin [ 81 , 98 ] and Cardenolide CL-43 [ 99 ] have been shown to inhibit HSF1 transcriptional activity in cancer cells. In addition, PW3405 [ 100 ] and Compound 1 [ 101 ] were discovered as inhibitors of HSF1 by inhibition of phosphorylation.…”