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Heat Shock Proteins of the 70-kDa family (HSP70s) do not cause cancer by themselves, but instead protect cells as they transform into cancer. These molecular chaperones bind numerous client proteins and utilize ATP hydrolysis to facilitate proper protein folding, formation of functional complexes and cellular localizations, or degradation of irreparably damaged proteins. Their transient upregulation by stressful situations avoids induction of programmed cell death. Continued upregulation of the mortalin, heat shock cognate (hsc70) and glucose regulated protein 78 (Grp78) support cancer development and progression by supporting pro-proliferative and metabolic functions and repressing pro-death functions of oncoproteins and tumor suppressor proteins. This review describes the discovery and development of a lead anti-cancer compound, sulfur heteroarotinoid A2 (SHetA2, NSC726189), which was originally developed to bind retinoic acid receptors, but was subsequently found to work independently of these receptors. The discovery and validation of mortalin, hsc70 and Grp78 as SHetA2 target proteins is summarized. The documented and hypothesized roles of these HSP70 proteins and their clients in the mechanism of SHetA2 inhibition of cancer without toxicity are discussed. Use of this mechanistic data to evaluate drug action in a cancer clinical trial and develop synergistic drug combinations is explained. Knowledge needed to optimize SHetA2 analogs for use in cancer therapy and prevention is proposed as future directions.

SHetA2 Attack on Mortalin and Colleagues in Cancer Therapy and Prevention