Small-molecule activating SIRT6 elicits therapeutic effects and synergistically promotes anti-tumor activity of vitamin D<sub>3</sub> in colorectal cancer

Shang, Jialin; Zhu, Zhehui; Chen, Yingyi; Song, Jinglue; Huang, Yuji; Song, Kun; Zhong, Jie; Xu, Xinyuan; Wei, Jiacheng; Wang, Cheng-Xiang; Cui, Long; Liu, Chenying; Zhang, Jian

doi:10.7150/thno.44043

Cited by 39 publications

(32 citation statements)

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“…1) 43,44 . Biochemical analysis of this activator revealed that it is robustly suppressed in cancer models and that it improves the quality of induced pluripotent stem cells derived from aging mice [45][46][47] . These findings highlight the potential of Sirt6 allosteric drug development.…”

Section: Introductionmentioning

confidence: 99%

Discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy

Wei

et al. 2021

Chem. Sci.

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Section: Introductionmentioning

confidence: 99%

Discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy

Wei

et al. 2021

Chem. Sci.

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“…Treatments for CRC include chemotherapies, endoscopic and surgical excision, targeted therapies, local ablative therapies, and immunotherapies 3 – 6 . Although there are multiple treatments, CRC still is the leading cause of cancer-related deaths 7 , 8 . Among various treatments, chemotherapies occupy an important role in advanced colorectal cancer, but chemotherapy drugs available in colorectal cancer are limited.…”

Section: Introductionmentioning

confidence: 99%

Utidelone inhibits growth of colorectal cancer cells through ROS/JNK signaling pathway

Huang

Tang

et al. 2021

Cell Death Dis

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Utidelone (UTD1), a novel microtubule stabilizing agent, is an epothilone B analogue which was produced by genetic engineering. UTD1 has exhibited broad antitumor activity in multiple solid tumors. However, its activity and mechanism in colorectal cancer (CRC) remain to be studied. In this study, UTD1 dramatically inhibited CRC cell proliferation (with 0.38 µg/ml, 0.77 µg/ml IC50 in RKO and HCT116, respectively) in vitro. Immunofluorescence staining showed that UTD1 induced the formation of microtubule bundling and asters in RKO cells. Flow cytometry analysis demonstrated that UTD1 induced cell cycle to arrest in G2/M phase, subsequent apoptosis. Significantly, UTD1 exhibited stronger effect on inducing apoptosis than paclitaxel and 5-FU, especially in HCT15 cells which is ABCB1 high-expression. UTD1 exposure cleaved caspase-3 and poly ADP-ribose polymerase (PARP), decreased mitochondrial membrane potential, released cytochrome c, increased the production of active oxygen and activated c-Jun N-terminal kinase (JNK), suggesting ROS/JNK pathway was involved in this process. Moreover, UTD1 inhibited tumor growth and was more effective and safer compared with paclitaxel and 5-FU in RKO xenograft in nude mice. Taken together, our findings first indicate that UDT1 inhibits tumor growth in CRC xenograft model and may be a promising agent for CRC treatment.

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“…MDL‐811 significantly inhibits proliferation on diverse colorectal cancer cell lines and patient‐derived organoids. Moreover, the in vivo antitumor efficacy of MDL‐811 was further demonstrated in HCT116 cell line‐ and patient‐derived xenografts, as well as in the APC min/+ spontaneous colorectal cancer model while no obvious body weight loss and other abnormal behavioral signs were observed 326 . Despite only modest in vivo activity, these results support a therapeutic benefit for cancer treatment by activating SIRT6.…”

Section: Sirt6 Modulatorsmentioning

confidence: 63%

Emerging roles of SIRT6 in human diseases and its modulators

Liu

Chen

Liu

et al. 2020

Medicinal Research Reviews

103

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The biological functions of sirtuin 6 (SIRT6; e.g., deacetylation, defatty‐acylation, and mono‐ADP‐ribosylation) play a pivotal role in regulating lifespan and several fundamental processes controlling aging such as DNA repair, gene expression, and telomeric maintenance. Over the past decades, the aberration of SIRT6 has been extensively observed in diverse life‐threatening human diseases. In this comprehensive review, we summarize the critical roles of SIRT6 in the onset and progression of human diseases including cancer, inflammation, diabetes, steatohepatitis, arthritis, cardiovascular diseases, neurodegenerative diseases, viral infections, renal and corneal injuries, as well as the elucidation of the related signaling pathways. Moreover, we discuss the advances in the development of small molecule SIRT6 modulators including activators and inhibitors as well as their pharmacological profiles toward potential therapeutics for SIRT6‐mediated diseases.

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Small-molecule activating SIRT6 elicits therapeutic effects and synergistically promotes anti-tumor activity of vitamin D₃ in colorectal cancer

Cited by 39 publications

References 0 publications

Discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy

Discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy

Utidelone inhibits growth of colorectal cancer cells through ROS/JNK signaling pathway

Emerging roles of SIRT6 in human diseases and its modulators

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Small-molecule activating SIRT6 elicits therapeutic effects and synergistically promotes anti-tumor activity of vitamin D3 in colorectal cancer

Cited by 39 publications

References 0 publications

Discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy

Discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy

Utidelone inhibits growth of colorectal cancer cells through ROS/JNK signaling pathway

Emerging roles of SIRT6 in human diseases and its modulators

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Small-molecule activating SIRT6 elicits therapeutic effects and synergistically promotes anti-tumor activity of vitamin D₃ in colorectal cancer