The novel HSP90 inhibitor AT13387 potentiates radiation effects in squamous cell carcinoma and adenocarcinoma cells

Abstract

Overexpression of heat shock protein 90 (HSP90) is associated with increased tumor cell survival and radioresistance. In this study we explored the efficacy of the novel HSP90 inhibitor AT13387 and examined its radiosensitizing effects in combination with gamma-radiation in 2D and 3D structures as well as mice-xenografts. AT13387 induced effective cytotoxic activity and radiosensitized cancer cells in monolayer and tumor spheroid models, where low drug doses triggered significant synergistic effects on cell survival together with radiation. Furthermore, AT13387 treatment resulted in G2/M-phase arrest and significantly reduced the migration capacity. The expression of selected client proteins involved in DNA repair, cell-signaling and cell growth was downregulated in vitro, though the expression of most investigated proteins recurred after 8–24 h. These results were confirmed in vivo where AT13387 treated tumors displayed effective downregulation of HSP90 and its oncogenic client proteins.In conclusion, our results demonstrate that AT13387 is a potent new cancer drug and effective radiosensitizer in vitro with an excellent in vivo efficacy. AT13387 treatment has the potential to improve external beam therapy and radionuclide therapy outcomes and restore treatment efficacy in cancers that are resistant to initial therapeutic regimes.

A novel HSP90 inhibitor with reduced hepatotoxicity synergizes with radiotherapy to induce apoptosis, abrogate clonogenic survival, and improve tumor control in models of colorectal cancer

“…Indeed, treatment of colorectal cancer cells with NW457 resulted in rapid degradation of ATM and CHK1, two essential upstream kinases of the DNA damage response. This is in accordance with findings of other studies, which showed that targeting HSP90 with small-molecule inhibitors induces the destabilization of different DNA damage response regulators, including ATM, CHK1, DNA-dependent protein kinase (DNA-PK), DNA repair protein RAD51 homologue 1 (RAD51), breast cancer 1 (BRCA1), and others [12, 13, 15, 19, 49, 57, 58]. Importantly, homologous recombination and non-homologous end joining, the two major mechanisms which operate to repair irradiation-induced DNA double strand breaks, appear to be affected to comparable extents [12, 13, 49, 59, 60].…”

“…The anti-tumor efficacy of HSP90 inhibition in combination with radiotherapy has rarely been examined in vivo , and data on HSP90 inhibitor-mediated radiosensitization in colorectal cancer models are scarce [49]. We therefore sought to elucidate the anti-tumor effects of NW457 in combination with radiotherapy in a heterotopic transplantation model of CT26 colorectal cancer cells on Balb/c mice.…”

Inhibition of heat shock protein 90 exerts an antitumour effect in angiosarcoma: involvement of the vascular endothelial growth factor signalling pathway

“…Ganetespib, a novel HSP90 inhibitor, exerts its competitive inhibitory effect by binding to the N‐terminal ATP‐binding site, and has been shown to have antitumour activity and lower hepatic and ocular toxicity compared with other HSP90 inhibitors . In addition, HSP90 inhibitors have attracted attention as sensitizers of cancer cells to both conventional chemotherapy and radiation therapy . Therefore, in our study, we investigated the role of HSP90 in the pathogenesis of angiosarcoma and whether the inhibition of HSP90 may have therapeutic potential.…”

Targeting EGFR and ALK in NSCLC: Current Evidence and Future Perspective

“…The hopes and concerns, about combination therapy with ALK-inhibitors and immunotherapy are pretty the same described with EGFR mutations, with a special interest in adverse events Ongoing but not recruiting [98] 10. …”