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The preclinical evaluation of the dual mTORC1/2 inhibitor INK-128 as a potential anti-colorectal cancer agent.
Cancer Biol Ther. 2015; 16(1):34-42.CB

Abstract

The colorectal cancer is the leading contributor of cancer-related mortality. Mammalian target of rapamycin (mTOR), existing in 2 complexes (mTORC1/2), is frequently dysregulated and constitutively activated in colorectal cancers. It represents an important drug target. Here we found that INK-128, the novel ATP-competitive kinase inhibitor of mTOR, blocked both mTORC1 and mTORC2 activation in colorectal cancer cells (both primary and transformed cells). The immunoprecipitation results showed that the assembly of mTORC1 (mTOR-Raptor association) and mTORC2 (mTOR-Rictor-Sin1 association) was also disrupted by INK-128. INK-128 inhibited colorectal cancer cell growth and survival, and induced both apoptotic and non-apoptotic cancer cell death. Further, INK-128 showed no effect on Erk/MAPK activation, while MEK/Erk inhibition by MEK-162 enhanced INK-128-induced cytotoxicity in colorectal cancer cells. Meanwhile, INK-128 downregulated Fascin1 (FSCN1)/E-Cadherin expressions and inhibited HT-29 cell in vitro migration. In vivo, daily INK-128 oral administration inhibited HT-29 xenograft growth in mice, which was further enhanced by MEK-162 administration. Finally, we found that INK-128 sensitized 5-fluorouracil-(5-FU)-mediated anti-HT-29 activity in vivo and in vitro. Thus, our preclinical studies strongly suggest that INK-128 might be investigated for colorectal cancer treatment in clinical trials.

Authors+Show Affiliations

a Department of Gastroenterology; Xuzhou Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine ; Xuzhou , China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25692620

Citation

Li, Chen, et al. "The Preclinical Evaluation of the Dual mTORC1/2 Inhibitor INK-128 as a Potential Anti-colorectal Cancer Agent." Cancer Biology & Therapy, vol. 16, no. 1, 2015, pp. 34-42.
Li C, Cui JF, Chen MB, et al. The preclinical evaluation of the dual mTORC1/2 inhibitor INK-128 as a potential anti-colorectal cancer agent. Cancer Biol Ther. 2015;16(1):34-42.
Li, C., Cui, J. F., Chen, M. B., Liu, C. Y., Liu, F., Zhang, Q. D., Zou, J., & Lu, P. H. (2015). The preclinical evaluation of the dual mTORC1/2 inhibitor INK-128 as a potential anti-colorectal cancer agent. Cancer Biology & Therapy, 16(1), 34-42. https://doi.org/10.4161/15384047.2014.972274
Li C, et al. The Preclinical Evaluation of the Dual mTORC1/2 Inhibitor INK-128 as a Potential Anti-colorectal Cancer Agent. Cancer Biol Ther. 2015;16(1):34-42. PubMed PMID: 25692620.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The preclinical evaluation of the dual mTORC1/2 inhibitor INK-128 as a potential anti-colorectal cancer agent. AU - Li,Chen, AU - Cui,Jian-Feng, AU - Chen,Min-Bin, AU - Liu,Chao-Ying, AU - Liu,Feng, AU - Zhang,Qian-De, AU - Zou,Jian, AU - Lu,Pei-Hua, PY - 2015/2/19/entrez PY - 2015/2/19/pubmed PY - 2015/11/10/medline KW - (S6K), p70S6K1 KW - (mTOR), mammalian target of rapamycin KW - (mTORC1), mTOR complex 1 KW - (mTORC2), mTOR complex 2 KW - Co-IP, co-immunoprecipitation KW - ECL, enhanced chemiluminescence KW - FSCN10, Fascin1 KW - HRP, horseradish peroxidase KW - INK-128 KW - PI, propidium iodide KW - SD, standard deviation (SD) KW - cell growth and migration KW - colorectal cancer KW - mTOR SP - 34 EP - 42 JF - Cancer biology & therapy JO - Cancer Biol Ther VL - 16 IS - 1 N2 - The colorectal cancer is the leading contributor of cancer-related mortality. Mammalian target of rapamycin (mTOR), existing in 2 complexes (mTORC1/2), is frequently dysregulated and constitutively activated in colorectal cancers. It represents an important drug target. Here we found that INK-128, the novel ATP-competitive kinase inhibitor of mTOR, blocked both mTORC1 and mTORC2 activation in colorectal cancer cells (both primary and transformed cells). The immunoprecipitation results showed that the assembly of mTORC1 (mTOR-Raptor association) and mTORC2 (mTOR-Rictor-Sin1 association) was also disrupted by INK-128. INK-128 inhibited colorectal cancer cell growth and survival, and induced both apoptotic and non-apoptotic cancer cell death. Further, INK-128 showed no effect on Erk/MAPK activation, while MEK/Erk inhibition by MEK-162 enhanced INK-128-induced cytotoxicity in colorectal cancer cells. Meanwhile, INK-128 downregulated Fascin1 (FSCN1)/E-Cadherin expressions and inhibited HT-29 cell in vitro migration. In vivo, daily INK-128 oral administration inhibited HT-29 xenograft growth in mice, which was further enhanced by MEK-162 administration. Finally, we found that INK-128 sensitized 5-fluorouracil-(5-FU)-mediated anti-HT-29 activity in vivo and in vitro. Thus, our preclinical studies strongly suggest that INK-128 might be investigated for colorectal cancer treatment in clinical trials. SN - 1555-8576 UR - https://www.unboundmedicine.com/medline/citation/25692620/The_preclinical_evaluation_of_the_dual_mTORC1/2_inhibitor_INK_128_as_a_potential_anti_colorectal_cancer_agent_ L2 - https://www.tandfonline.com/doi/full/10.4161/15384047.2014.972274 DB - PRIME DP - Unbound Medicine ER -