The Hsp90 facilitates proper folding of signaling proteins associated with cancer progression, gaining attention as a target for therapeutic intervention.

The clinical benefit of current anticancer regimens for lung cancer therapy is still limited due to moderate efficacy, drug resistance, and recurrence. Therefore, the development of effective anticancer drugs for first-line therapy and for optimal second-line treatment is necessary. Because the 90-kDa molecular chaperone heat shock protein (Hsp90) contributes to the maturation of numerous mutated or overexpressed oncogenic proteins, targeting Hsp90 may offer an effective anticancer therapy. Here, we investigated antitumor activities and toxicity of a novel deguelinderived C-terminal Hsp90 inhibitor, designated L80. L80 displayed significant inhibitory effects on the viability, colony formation, angiogenesis-stimulating activity, migration, and invasion of a panel of non-small cell lung cancer cell lines and their sublines with acquired resistance to paclitaxel with minimal toxicity to normal lung epithelial cells, hippocampal cells, vascular endothelial cells, and ocular cells. Biochemical analyses and molecular docking simulation revealed that L80 disrupted Hsp90 function by binding to the C-terminal ATP-binding pocket of Hsp90, leading to the disruption of the interaction between hypoxia-inducible factor (HIF)-1a and Hsp90, downregulation of HIF-1a and its target genes, including vascular endothelial growth factor (VEGF) and insulin-like growth factor 2 (IGF2), and decreased the expression of various Hsp90 client proteins. Consistent with these in vitro findings, L80 exhibited significant antitumor and antiangiogenic activities in H1299 xenograft tumors. These results suggest that L80 represents a novel C-terminal Hsp90 inhibitor with effective anticancer activities with minimal toxicities.

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Carfilzomib (CFZ) is a peptide epoxyketone proteasome inhibitor approved for the treatment of multiple myeloma (MM). Despite the remarkable efficacy of CFZ against MM, the clinical trials in patients with solid cancers yielded rather disappointing results with minimal clinical benefits. Rapid degradation of CFZ in vivo and its poor penetration to tumor sites are considered to be major factors limiting its efficacy against solid cancers. We previously reported that polymer micelles (PMs) composed of biodegradable block copolymers poly(ethylene glycol) (PEG) and poly(caprolactone) (PCL) can improve the metabolic stability of CFZ in vitro. Here, we prepared the CFZ-loaded PM, PEG-PCL-deoxycholic acid (CFZ-PM) and assessed its in vivo anticancer efficacy and pharmacokinetic profiles. Despite in vitro metabolic protection of CFZ, CFZ-PM did not display in vivo anticancer efficacy in mice bearing human lung cancer xenograft (H460) superior to that of the clinically used cyclodextrin-based CFZ (CFZ-CD) formulation. The plasma pharmacokinetic profiles of CFZ-PM were also comparable to those of CFZ-CD and the residual tumors that persisted in xenograft mice receiving CFZ-PM displayed an incomplete proteasome inhibition. In summary, our results showed that despite its favorable in vitro performances, the current CFZ-PM formulation did not improve in vivo anticancer efficacy and accessibility of active CFZ to solid cancer tissues over CFZ-CD. Careful consideration of the current results and potential confounding factors may provide valuable insights into the future efforts to validate the potential of CFZ-based therapy for solid cancer and to develop effective CFZ delivery strategies that can be used to treat solid cancers.

Despite several decades of intensive efforts to develop anti-cancer drugs and therapeutic strategies, lung cancer is still one of the main causes of cancer-related deaths worldwide. Deguelin, a natural plant product, has shown anti-cancer activities in skin, colon, breast and non-small cell lung (NSCLC) cancers. However, the potential side effects of deguelin could be an obstacle to its use in clinic. In the current study, we aimed to develop a derivative of deguelin with reduced potential side effects. We have synthesized a novel deguelin analog, compound A, and evaluated its effects on cancer and normal bronchial epithelial cell proliferation, survival, and colony formation by the MTT, FACS, and/or anchorage-dependent and -independent colony forming assays. Mechanisms underlying anti-tumor effects of compound A were investigated by Western blot, and RT-PCR. Treatment with compound A inhibited cancer cell proliferation and colony formation, promoted cell cycle arrest and induced apoptosis. Compound A also suppressed the expression of HIF-1α protein and its target gene, VEGF, in NSCLC cells. Administration of compound A to NSCLC xenograft-bearing mice significantly decreased tumor growth by inhibiting tumor angiogenesis and by inducing apoptosis. In its action mechanism, compound A was involved in binding to the ATP-binding pocket of HSP90, leading to the suppression of HSP90 function. These collective results suggest that a novel deguelin derivative, compound A, has a strong potential as an anti-cancer drug. Citation Format: Su-Chan Lee, Ju-Sung Lee, Seung-Yeob Hyun, Hoon Choi, Hongchan An, Kyu-Won Kim, Young-Ger Suh, Ho-Young Lee. Antitumor effect of a Compound A, a derivative of a naturally occurring rotenoid deguelin, by inhibition of ATP binding to heat shock protein 90. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3196. doi:10.1158/1538-7445.AM2014-3196