Abstract
Indibulin, a synthetic inhibitor of tubulin assembly, has shown promising anticancer activity with a minimal neurotoxicity in preclinical animal studies and in Phase I clinical trials for cancer chemotherapy. Using time-lapse confocal microscopy, we show that indibulin dampens the dynamic instability of individual microtubules in live breast cancer cells. Indibulin treatment also perturbed the localization of end-binding proteins at the growing microtubule ends in MCF-7 cells. Indibulin reduced inter-kinetochoric tension, produced aberrant spindles, activated mitotic checkpoint proteins Mad2 and BubR1, and induced mitotic arrest in MCF-7 cells. Indibulin-treated MCF-7 cells underwent apoptosis-mediated cell death. Further, the combination of indibulin with an anticancer drug vinblastine was found to exert synergistic cytotoxic effects on MCF-7 cells. Interestingly, indibulin displayed a stronger effect on the undifferentiated neuroblastoma (SH-SY5Y) cells than the differentiated neuronal cells. Unlike indibulin, vinblastine and colchicine produced similar depolymerizing effects on microtubules in both differentiated and undifferentiated SH-SY5Y cells. The data indicated a possibility that indibulin may reduce chemotherapy-induced peripheral neuropathy in cancer patients.
Highlights
Indibulin, N-(pyridin-4-yl)-[1-(4-chlorbenzyl)-indol-3-yl]-glyoxyl-amide (D-24851) (Fig. 1A) has been found to have a potent activity towards a wide variety of cancer cell lines including colon, ovarian, cervix, brain, and pancreatic cancer cell lines[1,2]
Indibulin inhibited the proliferation of MCF-7 cells with a half-maximal inhibitory concentration of 150 ± 13 nM (Fig. 1B)
The polymeric tubulin to soluble tubulin ratio was determined to be 2.3 ± 0.6, 1.6 ± 0.4 (p < 0.05), 1.1 ± 0.2 (p < 0.05), 0.9 ± 0.2 (p < 0.05) in the absence and presence of 150, 450 and 900 nM indibulin, respectively by Western blotting suggesting that indibulin treatment depolymerized microtubules in MCF-7 cells (Fig. 2B)
Summary
N-(pyridin-4-yl)-[1-(4-chlorbenzyl)-indol-3-yl]-glyoxyl-amide (D-24851) (Fig. 1A) has been found to have a potent activity towards a wide variety of cancer cell lines including colon, ovarian, cervix, brain, and pancreatic cancer cell lines[1,2]. It retained its efficacy in multidrug-resistant cells lines that were resistant towards paclitaxel, vincristine, or doxorubicin suggesting that indibulin might not be a substrate of P-gp pumps[1]. Our data showed that indibulin exerted a differential effect on differentiated and undifferentiated neuronal cell lines and could lead to reduced neurotoxicity as compared to other anti-tubulin agents
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