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Inhibitor of the spindle assembly checkpoint surpasses apoptosis sensitizer in synergy with taxanes

Teng-Long Han, Zhi-Xin Jiang, Yun-Tian Li, Deng-Shan Wu, Jun Ji, Hu Lin, Bin Hu, Hang Sha
doi: https://doi.org/10.1101/414359
Teng-Long Han
1The 305th Hospital of the People’s Liberation Army, Beijing 100017, China
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  • For correspondence: hantenglong@hotmail.com shahang5835@hotmail.com
Zhi-Xin Jiang
1The 305th Hospital of the People’s Liberation Army, Beijing 100017, China
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Yun-Tian Li
1The 305th Hospital of the People’s Liberation Army, Beijing 100017, China
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Deng-Shan Wu
1The 305th Hospital of the People’s Liberation Army, Beijing 100017, China
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Jun Ji
1The 305th Hospital of the People’s Liberation Army, Beijing 100017, China
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Hu Lin
1The 305th Hospital of the People’s Liberation Army, Beijing 100017, China
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Bin Hu
1The 305th Hospital of the People’s Liberation Army, Beijing 100017, China
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Hang Sha
1The 305th Hospital of the People’s Liberation Army, Beijing 100017, China
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  • For correspondence: hantenglong@hotmail.com shahang5835@hotmail.com
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Abstract

The antitumor effect of taxanes have been attributed to their ability to induce mitotic arrest through activation of the spindle assembly checkpoint. Cell death following prolonged mitotic arrest is mediated by the intrinsic apoptosis pathway. Thus, apoptosis sensitizers which inhibit antiapoptotic Bcl-2 family proteins has been shown to enhance taxanes-induced cell death. By contrast, spindle checkpoint disruption facilitates mitotic slippage and is thought to promote taxanes resistance. Notably, other modes of cell death also contribute to treatment outcomes. Here we show that inhibition of the spindle checkpoint suppresses taxanes induced apoptosis but increases terminal growth arrest of tumor cells with features of cellular senescence. By using clonogenic assay which measures the net result of multiple forms of cell death and is more reflective of therapeutic response, our finding suggests apoptosis is not a major determinant of antitumor efficacy of taxanes, whereas spindle checkpoint inhibitor displays a long-term advantage over apoptosis sensitizer in blocking colony outgrowth of tumor cells when combined with different microtubule toxins, therefore represents a superior therapeutic strategy.

SIGNIFICANCE Apoptosis has long been regarded as the primary mechanism of anti-cancer efficacy of taxanes, while the role of the spindle assembly checkpoint (SAC) in treatment response to taxanes has been controversial. Either apoptosis sensitizer or inhibitor of SAC has been reported to synergize with taxanes. While inhibitor of antiapoptotic proteins potentiates taxanes induced apoptosis, inhibitor of SAC suppresses apoptosis by facilitating mitotic slippage, that is why it is implicated in taxanes resistance. By demonstrating that apoptotic rates are not associate with long-term treatment response, not only do we find that inhibitor of SAC displays a long-term advantage over apoptosis sensitizer in combination with taxanes, but we also resolve the dispute around the role of SAC in cellular response to taxanes.

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Posted September 11, 2018.
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Inhibitor of the spindle assembly checkpoint surpasses apoptosis sensitizer in synergy with taxanes
Teng-Long Han, Zhi-Xin Jiang, Yun-Tian Li, Deng-Shan Wu, Jun Ji, Hu Lin, Bin Hu, Hang Sha
bioRxiv 414359; doi: https://doi.org/10.1101/414359
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Inhibitor of the spindle assembly checkpoint surpasses apoptosis sensitizer in synergy with taxanes
Teng-Long Han, Zhi-Xin Jiang, Yun-Tian Li, Deng-Shan Wu, Jun Ji, Hu Lin, Bin Hu, Hang Sha
bioRxiv 414359; doi: https://doi.org/10.1101/414359

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