Abstract
Microtubule inhibitors are invaluable tools in cancer chemotherapy: taxanes and vinca alkaloids have been successfully used in the clinic over the past thirty years against a broad range of tumors. However, two factors have limited the effectiveness of microtubule inhibitors: toxicity and resistance. In particular, the latter is highly unpredictable, variable from patient to patient and is believed to be the cause of treatment failure in most cases of metastatic cancers. For these reasons, there is an increasing demand for new microtubule inhibitors that can overcome resistance mechanisms and that, at the same time, have reduced side effects. Here we present a novel microtubule inhibitor, 4SC-207, which shows strong anti-proliferative activity in a large panel of tumor cell lines with an average GI50 of 11nM. In particular, 4SC-207 is active in multi-drug resistant cell lines, such as HCT-15 and ACHN, suggesting that it is a poor substrate for drug efflux pumps. 4SC-207 inhibits microtubule growth in vitro and in vivo and promotes, in a dose dependent manner, a mitotic delay/arrest, followed by apoptosis or aberrant divisions due to chromosome alignment defects and formation of multi-polar spindles. Furthermore, preliminary data from preclinical studies suggest low propensity towards bone marrow toxicities at concentrations that inhibit tumor growth in paclitaxel-resistant xenograft models. In summary, our results suggest that 4SC-207 may be a potential anti-cancer agent.
Highlights
Microtubule inhibitors (MTIs) have been very successful in cancer therapy against a number of tumors: taxanes are commonly used in the treatment of breast and ovarian cancers while vinca alkaloids have been very effective in the treatment of hematological malignancies [1]
Taxanes and vinca alkaloids are highly effective anti-cancer agents and are extensively used in standard firstline chemotherapy, the development of resistance often renders them useless, in the context of secondary or metastatic cancers. For this reason there is a strong need for new chemotherapeutic agents that could provide effective treatment in second-line therapy, or whenever classical MTIs fail
We identify 4SC-207 that could respond to such demands. 4SC-207 belongs to the chemical class of tetrahydrothieno pyridines and so far this compound class had not been described to have anti-mitotic or microtubule inhibiting activities
Summary
Microtubule inhibitors (MTIs) have been very successful in cancer therapy against a number of tumors: taxanes are commonly used in the treatment of breast and ovarian cancers while vinca alkaloids have been very effective in the treatment of hematological malignancies [1].the efficacy of MTIs has been limited on one hand by toxicities, e.g. neutropenia and peripheral neuropathies [2,3], and on the other hand by the development of drug resistance [4,5]. While side effects are well understood and are usually manageable by dose reduction and/or dose interval, drug resistance poses problems to long-term usage of MTIs and has been estimated to be the cause for treatment failure in >90% of patients with metastatic disease [6]. Microtubules are polymers composed of α,β tubulin dimers that can exist in a growing or a shrinking phase. This dynamic behavior allows microtubules to fulfill most of their functions that range from intracellular transport to cell shape maintenance, from cell polarity to cell signaling and cell division [7,8]
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