The HSP70 Modulator MAL3-101 Inhibits Merkel Cell Carcinoma

Abstract

Merkel Cell Carcinoma (MCC) is a rare and highly aggressive neuroendocrine skin cancer for which no effective treatment is available. MCC represents a human cancer with the best experimental evidence for a causal role of a polyoma virus. Large T antigens (LTA) encoded by polyoma viruses are oncoproteins, which are thought to require support of cellular heat shock protein 70 (HSP70) to exert their transforming activity. Here we evaluated the capability of MAL3-101, a synthetic HSP70 inhibitor, to limit proliferation and survival of various MCC cell lines. Remarkably, MAL3-101 treatment resulted in considerable apoptosis in 5 out of 7 MCC cell lines. While this effect was not associated with the viral status of the MCC cells, quantitative mRNA expression analysis of the known HSP70 isoforms revealed a significant correlation between MAL3-101 sensitivity and HSC70 expression, the most prominent isoform in all cell lines. Moreover, MAL3-101 also exhibited in vivo antitumor activity in an MCC xenograft model suggesting that this substance or related compounds are potential therapeutics for the treatment of MCC in the future.

Dihydropyrimidinones and -thiones with improved activity against human polyomavirus family members

“…MAL3-101, the parent lead structure for SMAL and all of the compounds reported herein, was used as a positive control as this dihydropyrimidinone inhibits the growth of cancer cells both in vitro and in vivo . 8,23,24 As anticipated, MAL3-101 inhibited the growth of the two cancer lines with a GI 50 of 6.0-13 μM (Table 2). In contrast, all of the newly prepared compounds were significantly less toxic, with GI 50 values of 62-124 μM.…”

Heat shock protein defenses in the neocortex and allocortex of the telencephalon

“…In order to examine the functional consequences of the MG132-induced increase in Hsp70 and Hsc70, we treated neo- and allocortical cultures with the Hsp70/Hsc70 inhibitors VER155008 (Chatterjee et al, 2013; Macias et al, 2011; Massey et al, 2010; Saykally et al, 2012; Williamson et al, 2009) and MAL3-101 (Adam et al, 2014; Braunstein et al, 2011; Hatic et al, 2012; Huryn et al, 2011; Kilpatrick et al, 2013). MG132 toxicity was synergistically exacerbated by these two mechanistically different Hsp70/Hsc70 inhibitors in both neo- and allocortical neurons, but the effect sizes were consistently larger for allocortex according to the MAP2 neuron viability assay (Fig.…”

“…474790). Hsp70/Hsc70 activity was inhibited with the previously characterized compounds VER155008 (R&D Systems, Minneapolis, MN; Chatterjee et al, 2013; Massey et al, 2010; Saykally et al, 2012; Schlecht et al, 2013) and MAL3-101 (Adam et al, 2014; Braunstein et al, 2011; Hatic et al, 2012; Huryn et al, 2011; Kilpatrick et al, 2013). Hsp70 activity was enhanced with 115-7c (MAL1-271) (Kilpatrick et al, 2013; Wisen et al, 2010).…”

Chemical Tools to Investigate Mechanisms Associated with HSP90 and HSP70 in Disease

“…MAL3-101 and derivatives bind to the NBD of HSP70 in a region previously implicated in J protein interactions (Wisen et al, 2010). MAL3-101 showed cellular activity in Merkel cell carcinoma cell lines (Adam et al, 2014) and multiple myeloma (Braunstein et al, 2011) indicating a role for HSP70 in these cancers. MAL3-101 was also used as a chemical probe to investigate the role of HSP70 in the anti-apoptotic phenotype of small cell lung carcinoma (Rodina et al, 2007).…”