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The multi-targeted kinase inhibitor sunitinib induces apoptosis in colon cancer cells via PUMA.

ABSTRACT: Constitutive activation of pro-survival kinases has become a promising target of small molecules with an increasing interest in developing multi-targeted agents. The mechanisms underlying the responsiveness to most agents targeting cancer specific survival pathways are still poorly understood but critical for their clinical application. In this study, we found that sunitinib, a small molecule inhibitor of multiple tyrosine kinases including VEGFRs and PDGFRs induces apoptosis and inhibits cell growth in colon cancer cells in cell culture and xenograft models via the BH3-only protein PUMA. Sunitinib treatment induced PUMA transcription via the AKT/FoxO3a axis. PUMA, BH3 mimetics, or 5-Flurourical sensitized colon cancer cells to sunitinib-induced apoptosis. Furthermore, PUMA was induced by sunitinib treatment in xenograft tumors, and deficiency in PUMA significantly suppressed the anti-tumor effects of sunitinib. Our study suggests that PUMA-mediated apoptosis is important for the therapeutic responses to sunitinib, and activation of the mitochondrial pathway by BH3 mimetics or PUMA manipulation may be useful for improving the antitumor activity of sunitinib. Modulation of PUMA and selective Bcl-2 family members might be potential biomarkers for predicting sunitinib responses.

SUBMITTER: Sun J

PROVIDER: S-EPMC3422222 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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The multi-targeted kinase inhibitor sunitinib induces apoptosis in colon cancer cells via PUMA.

Sun Jing J Sun Quanhong Q Brown Matthew F MF Dudgeon Crissy C Chandler Julie J Xu Xiang X Shu Yongqian Y Zhang Lin L Yu Jian J

PloS one 20120817 8

Constitutive activation of pro-survival kinases has become a promising target of small molecules with an increasing interest in developing multi-targeted agents. The mechanisms underlying the responsiveness to most agents targeting cancer specific survival pathways are still poorly understood but critical for their clinical application. In this study, we found that sunitinib, a small molecule inhibitor of multiple tyrosine kinases including VEGFRs and PDGFRs induces apoptosis and inhibits cell g ...[more]

PMID: 22912816

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Project description:Simple Summary AF8c, a lapatinib hybrid quinazoline-based EGFR/HER2 inhibitor, was chosen to scrutinize its antiproliferative activity in colorectal cancer (CRC) cells. We found that AF8cinduced apoptosis in CRC cells via diverse mechanisms. In addition to inhibiting the phosphorylation of the ErbB family, AF8c increased the mRNA and protein levels of death receptor 5 (DR5) in vitro and in vivo. In addition, AF8c upregulated several ER stress proteins and the redox-sensitive nuclear respiratory factor 2 alpha subunit (Nrf2) in a p53-dependent manner. We also found that the AF8c-induced increase in the levels of Nrf2, DR5, and apoptosis was diminished by p53 downregulation or knockdown. Furthermore, AF8c showed higher antiproliferative activity than lapatinib in the CRC mouse model in vivo. Therefore, our results suggest AF8c as a highly effective polypharmacological small molecule with an encouraging safety profile, both in vitro and in vivo, for further evaluation as a treatment of CRC. Abstract Our team has previously reported a series of quinazoline-based lapatinib hybrids as potent kinase-targeting anticancer agents. Among them, AF8c showed a relatively safe profile in colorectal cancer (CRC) cells. In this study, we delineate a novel anticancer activity of AF8c in CRC cells. AF8c mediated p53-dependent apoptosis of CRC cells via the generation of endoplasmic reticulum (ER) stress and reactive oxygen species (ROS), as well as activation of nuclear respiratory factor 2 alpha subunit (Nrf2) and death receptor 5 (DR5), among others. The silencing of DR5 attenuated the expression levels of Nrf2 and partially inhibited AF8c-induced apoptosis. Additionally, upregulation of Nrf2 by AF8c evoked apoptosis through a decrease in antioxidant levels. Treatment of a CRC mice model with AF8c also resulted in the upregulation of DR5, Nrf2, and CHOP proteins, subsequently leading to a significant decrease in tumor burden. In comparison with lapatinib, AF8c showed higher cellular antiproliferative activity at the tested concentrations in CRC cells and synergized TRAIL effects in CRC cells. Overall, our results suggest that AF8c-induced apoptosis may be associated with DR5/Nrf2 activation through ER stress and ROS generation in CRC cells. These findings indicate that AF8c represents a promising polypharmacological molecule for the treatment of human CRC.

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The multi-targeted kinase inhibitor sunitinib induces apoptosis in colon cancer cells via PUMA.

Publications

The multi-targeted kinase inhibitor sunitinib induces apoptosis in colon cancer cells via PUMA.

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