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Cancer Lett. 2018 Jul 10;426:25-36. doi: 10.1016/j.canlet.2018.03.041. Epub 2018 Mar 30.

A novel tropomyosin-related kinase A inhibitor, KK5101 to treat pancreatic cancer.

Author information

1
Department of Drug Development, College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon, 400-712, Republic of Korea.
2
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Hwarangro 14-gil 5, Seongbuk-gu, Seoul, 02792, Republic of Korea.
3
Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura, 35516, Egypt.
4
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Hwarangro 14-gil 5, Seongbuk-gu, Seoul, 02792, Republic of Korea.
5
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Hwarangro 14-gil 5, Seongbuk-gu, Seoul, 02792, Republic of Korea. Electronic address: gkeum@kist.re.kr.
6
Department of Drug Development, College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon, 400-712, Republic of Korea. Electronic address: hongs@inha.ac.kr.

Abstract

Tropomyosin-related kinase A (TrkA) plays important roles in tumor cell growth and survival signaling and contributes to chemo-resistance in pancreatic cancer. Therefore, we developed KK5101, a novel TrkA target inhibitor and assessed its anti-cancer effects and investigated underlying mechanism of action in pancreatic cancer. KK5101 was characterized to inhibit TrkA selectively and potently by protein binding assay. It effectively inhibited the growth and proliferation of pancreatic cancer cells. Also, KK5101 increased apoptosis with loss of mitochondrial membrane potential, as evidenced by increases of cytochrome c releases. It increased numbers of TUNEL-positive apoptotic cells, and cell death including early and late apoptosis by Annexin V assay. In addition, activation of the TrkA signaling cascades including p-AKT, p-MEK, and p-STAT3 were inhibited by KK5101 treatment in vitro, as well as ex vivo tumor spheroid models, resulting in potent induction of apoptosis. Importantly, KK5101 also significantly attenuated tumor growth of in vivo pancreatic cancer models. These findings indicate that KK5101 may exert antitumor effects by directly affecting cancer cell growth or survival via inhibition of TrkA signaling pathway. We therefore suggest that KK5101 is a novel therapeutic candidate for treating pancreatic cancer.

KEYWORDS:

Apoptosis; KK5101; Pancreatic cancer; Tropomyosin-related kinase A (TrkA)

PMID:
29605512
DOI:
10.1016/j.canlet.2018.03.041
[Indexed for MEDLINE]

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