Abstract
Microtubule-binding agents, such as taxanes and vinca alkaloids, are used in the treatment of cancer. The limitations of these treatments, such as resistance to therapy and the need for intravenous administration, have encouraged the development of new agents. MPT0B271 (N-[1-(4-Methoxy-benzenesulfonyl)-2,3-dihydro-1H-indol-7-yl]-1-oxy-isonicotinamide), an orally active microtubule-targeting agent, is a completely synthetic compound that possesses potent anticancer effects in vitro and in vivo. Tubulin polymerization assay and immunofluorescence experiment showed that MPT0B271 caused depolymerization of tubulin at both molecular and cellular levels. MPT0B271 reduced cell growth and viability at nanomolar concentrations in numerous cancer cell lines, including a multidrug-resistant cancer cell line NCI/ADR-RES. Further studies indicated that MPT0B271 is not a substrate of P-glycoprotein (P-gp), as determined by flow cytometric analysis of rhodamine-123 (Rh-123) dye efflux and the calcein acetoxymethyl ester (calcein AM) assay. MPT0B271 also caused G2/M cell-cycle arrest, accompanied by the up-regulation of cyclin B1, p-Thr161 Cdc2/p34, serine/threonine kinases polo-like kinase 1, aurora kinase A and B and the downregulation of Cdc25C and p-Tyr15 Cdc2/p34 protein levels. The appearance of MPM2 and the nuclear translocation of cyclin B1 denoted M phase arrest in MPT0B271-treated cells. Moreover, MPT0B271 induced cell apoptosis in a concentration-dependent manner; it also reduced the expression of Bcl-2, Bcl-xL, and Mcl-1 and increased the cleavage of caspase-3 and -7 and poly (ADP-ribose) polymerase (PARP). Finally, this study demonstrated that MPT0B271 in combination with erlotinib significantly inhibits the growth of the human non-small cell lung cancer A549 cells as compared with erlotinib treatment alone, both in vitro and in vivo. These findings identify MPT0B271 as a promising new tubulin-binding compound for the treatment of various cancers.
Highlights
Even though microtubule-targeting agents are used clinically to treat patients with neoplastic disease, they have substantial drawbacks such as the development of resistance over time.[5]
Signal transducer and activator of transcription 3 (STAT3) regulates the expression of various genes including Bcl-xL, Mcl-1, cyclin D1, and p53, which regulate cell-cycle progression, cell survival, and proliferation.[15,16]
Targeted therapies directed at blocking Epidermal growth factor receptor (EGFR) function are attractive potential therapeutics for cancer.[19]
Summary
Even though microtubule-targeting agents are used clinically to treat patients with neoplastic disease, they have substantial drawbacks such as the development of resistance over time.[5]. Epidermal growth factor receptor (EGFR), a transmembrane glycoprotein, is frequently overexpressed in human tumors such as breast, ovarian, prostate, pancreatic, and non-small cell lung cancer (NSCLC). This overexpression is correlated with poor prognosis and worse clinical outcome. Clinical results have demonstrated that erlotinib monotherapy showed a survival benefit in comparison with gemcitabine for patients with NSCLC or pancreatic cancer, resistance to erlotinib reduces its efficacy.[20,21] The T790M point mutation in EGFR causes a conformational change at the ATP binding pocket, decreasing the affinity between erlotinib and EGFR and leading to acquired/secondary resistance.[22,23]
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