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Significant off-target effects of postulated IGF-1R inhibitor picropodophyllin (PPP) in vitro

Wu, Xuping and Sooman, Linda and Wickström, Malin and Frynäs, Mårten and Dyrager, Christine and Lennartsson, Johan and Gullbo, Joachim (2013) Significant off-target effects of postulated IGF-1R inhibitor picropodophyllin (PPP) in vitro. Molecular Cancer Therapeutics.

Abstract

The insulin-like growth factor-1 (IGF-1) and its receptors play an important role in the transformation and progression of several malignancies. Several inhibitors of this pathway have been developed and evaluated in clinical trials, a majority of which with discouraging results and several drug candidates have been abandoned. The cyclolignan picropodophyllin (PPP) has been described as a potent and selective inhibitor of IGF-1R, and is currently investigated in clinical trials from which early reports suggest low toxicity and signs of clinical activity. In this report the cytotoxic activity of PPP and sets of standard agents were examined, compared and put in relation to the phosphorylation and expression levels of IGF-1R. The activity of PPP was unrelated to presence or spontaneous phosphorylation of IGF-1R, but correlated in all systems to activity of tubulin inhibitors. This led us to hypothesize that PPP’s effects in these cells were related to tubulin interaction rather than IGF-1R inhibition. Indeed PPP could destabilize microtubule assembly at concentrations needed to induce cytotoxicity cells, and at concentrations achievable in patients. Interestingly, PPP did also inhibit downstream signaling from tyrosine kinase receptors, including the serine/threonine kinase Akt. We could demonstrate that this surprising activity, also reported in previous reports on PPP but then attributed to IGF-1R inhibition, was associated with downregulation of the EGF receptor (EGFR). In summary, this study challenges previous reports on the cyclolignan PPP as an IGF-1R tyrosine kinase inhibitor and instead suggests that PPP targets, directly or indirectly, the microtubule network.

Item Type: Article
Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/7359

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