Deguelin analogues, L80 and SH-1242, inhibit Hsp90 activity and exert potent anticancer efficacy with limited toxicities in non-small cell lung cancer (NSCLC)

Abstract

Lung cancer is one of the leading causes of death among many types of cancers in South Korea as well as worldwide. More than 85% of lung cancer patients are diagnosed with non-small cell lung cancer (NSCLC) and treated with chemotherapy, one of the common treatments. Unfortunately, prolonged treatment of chemotherapy could make human bodies resistant to the drugs used in chemotherapy and exposes organs to toxicities, which have led many types of research to focus on the development of anticancer drugs that target specific molecules particularly in cellular signal transduction pathways activated in cancer. However, only a small population of patients respond to these medicines and even patients initially responsive to these drugs show resistance after prolonged treatment. For these reasons, the development of new therapeutic drugs that target identified molecular mechanisms and exert anti-cancer activities in cancer cells both naïve and resistant to chemotherapy is urgently needed. Numerous proteins involved in the signal transduction pathways of cancer cells serve as client proteins of Hsp90. Many studies have reported that inhibition of the function of Hsp90 caused the structural instabilities of its client proteins, resulting in anti-cancer effects. Additionally, targeting of Hsp90 has been proposed to overcome resistance to agents for chemotherapy and targeted therapy. Classical Hsp90 inhibitors bind to ATP binding pockets in the N-terminal domain, consequently stopping the process of the folding machinery of client proteins which leads to the proteasomal degradation of those proteins. Unfortunately, clinical trials of these N-terminal inhibitors failed due to the lack of sufficiently promising activity and severe toxicities in clinical tests. Deguelin, a natural compound, demonstrated anti-proliferative, anti-metastatic, and apoptotic effects on cancer. The mechanism of action is that deguelin binds to the ATP-binding pocket of Hsp90, causing interference to the interaction between Hsp90 and their client proteins. Despite the promising anticancer activity of deguelin, potential toxicities such as Parkinsons disease and retinal toxicity hinder its clinical use in the clinic. Therefore, I hypothesized that deguelin analogues with stronger efficacy or less toxicity than that of deguelin would have a good chance of advancing to clinical trials. In this study, I selected two deguelin analogues, designated as L80 and SH-1242, and investigated their antitumor activities and toxicity. Both compounds inhibited cell viability, anchorage-dependent and -independent colony formation, angiogenesis-stimulating activity in non-small cell lung cancer (NSCLC) cells and their sublines with acquired resistance to paclitaxel or lincitinib. Consistent with these in vitro results, L80 and SH-1242 significantly inhibited tumor growth and antiangiogenic effects in xenograft models. They also displayed less toxicity to normal epithelial, vascular endothelial, vascular, retinal pigment epithelial, and mouse hippocampal cells than deguelin. Also, SH-1242 significantly reduced the inhibition of tyrosine hydroxylase immunoreactivity in the substantial nigra in rats. In terms of their mechanism of action, they are predicted to bind to the potential ATP-binding pocket in the C-terminal of Hsp90, causing the disruption of the interaction between Hsp90 and its client proteins. A series of processes resulted in the decreased expression of the client proteins. These results suggest that L80 and SH-1242 could be novel C-terminal inhibitors of Hsp90 with minimal toxicities. As major concerns associated with deguelin are potential toxicities, especially Parkinsons disease and retinal toxicity, the toxicities of L80 and SH-1242 will need to be further examined prior to clinical use. It will also be necessary to synthesize additional compounds without the potential neuronal toxicity based on these compounds.