BackgroundDespite an ever-improving understanding of the molecular biology of cancer, the treatment of most cancers has not changed dramatically in the past three decades and drugs that do not discriminate between tumor cells and normal tissues remain the mainstays of anticancer therapy. Since Hsp90 is typically involved in cell proliferation and survival, this is thought to play a key role in cancer, and Hsp90 has attracted considerable interest in recent years as a potential therapeutic target.MethodsWe focused on the interaction of Hsp90 with its cofactor protein p60/Hop, and engineered a cell-permeable peptidomimetic, termed "hybrid Antp-TPR peptide", modeled on the binding interface between the molecular chaperone Hsp90 and the TPR2A domain of Hop.ResultsIt was demonstrated that this designed hybrid Antp-TPR peptide inhibited the interaction of Hsp90 with the TPR2A domain, inducing cell death of breast, pancreatic, renal, lung, prostate, and gastric cancer cell lines in vitro. In contrast, Antp-TPR peptide did not affect the viability of normal cells. Moreover, analysis in vivo revealed that Antp-TPR peptide displayed a significant antitumor activity in a xenograft model of human pancreatic cancer in mice.ConclusionThese results indicate that Antp-TPR peptide would provide a potent and selective anticancer therapy to cancer patients.
Interleukin-4 receptor a (IL-4Ra) chain is highly expressed on the surface of various human solid tumors. We designed a novel hybrid peptide termed IL-4Ra-lytic peptide that targets the IL-4Ra chain. The IL-4Ra-lytic peptide contains a target moiety to bind to IL-4Ra and a cellular toxic lytic peptide that selectively kills cancer cells. The anticancer activity of the IL-4Ra-lytic peptide was evaluated in vitro and in vivo. It was found that the IL-4Ra-lytic peptide has cytotoxic activity in cancer cell lines expressing IL-4Ra, determined by quantitative real-time PCR. The IC 50 ratios of the lytic peptide to the IL-4Ra-lytic peptide correlated well with the expression levels of IL-4Ra on cancer cells (r ¼ 0.80). In addition, IL-4Ra-lytic peptide administered either intratumoraly or intravenously significantly inhibited tumor growth in xenograft model of human pancreatic cancer (BXPC-3) in mice. These results indicate that the IL-4Ra-lytic peptide generated in this study has a potent and selective anticancer potential against IL-4Ra-positive solid cancers. Mol Cancer Ther; 11(1); 235-43. Ó2011 AACR.
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