한빛사논문
- 조회888
Shalini V. Gowda a,1, Na Young Kim b,1, Kachigere B. Harsha a, Darshini Gowda a, Rajaghatta N. Suresh a, Amudha Deivasigamani c, Chakrabhavi Dhananjaya Mohan d, Kam Man Hui c, Gautam Sethi e, Kwang Seok Ahn b, Kanchugarakoppal S. Rangappa a
aDepartment of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, Karnataka, India
bDepartment of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
cDivision of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore 169610, Singapore
dFEST Division, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226 001, Uttar Pradesh, India
eDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
1These authors contributed equally to this work.
Corresponding authors : Kam Man Hui, Gautam Sethi, Kwang Seok Ahn, Kanchugarakoppal S. Rangappa
Abstract
Introduction: Hepatocellular carcinoma (HCC) is a fatal cancer that is often diagnosed at the advanced stages which limits the available therapeutic options. The interaction of HGF with c-MET (a receptor tyrosine kinase) results in the activation of c-MET which subsequently triggers the PI3K/Akt/mTOR axis. Overexpression of c-MET in HCC tissues has been demonstrated to contribute to tumor progression and metastasis.
Objectives: We aimed to synthesize triazole-indirubin conjugates, examine their growth suppressor efficacy in cell-based assays, and investigate the antitumor as well as antimetastatic activity of lead cytotoxic agent in the orthotopic mice model.
Methods: New triazole-indirubin hybrids were synthesized in a multi-step reaction. The cytotoxicity, apoptogenic, and antimigratory effect of the new compound (CRI9) was evaluated using MTT assay, cell cycle analysis, annexin-V/PI assay, TUNEL assay, and wound healing assay. The effect of CRI9 on the operation of the HGF/c-MET/PI3K/Akt/mTOR axis was examined with western blotting and transfection experiments. Acute toxicity, antitumor, and antimetastatic activity of CRI9 were examined in NCr nude mice. The expression of c-MET/PI3K/Akt/mTOR, CD31, and Ki-67 was examined by immunohistochemistry and western blotting.
Results: Among the new compounds, CRI9 consistently displayed potent cytotoxicity against HGF-induced HCC cells. CRI9 induced apoptosis as evidenced by increased sub G1 cells, annexin-V+/PI+ cells, TUNEL+ cells, and cleavage of procaspase-3 and PARP. CRI9 inhibited HGF-induced phosphorylation of c-METY1234/1235 and subsequently suppressed the PI3K/Akt/mTOR axis. Also, depletion of c-MET or inhibition of c-MET by CRI9 resulted in suppression of the PI3K/Akt/mTOR axis. CRI9 showed no toxic effects in NCr nude mice and displayed a potent antitumor and antimetastatic effect in the orthotopic HCC mice model. CRI9 also reduced the levels of phospho-c-MET, CD31, and Ki-67 and suppressed the activation of the PI3K/Akt/mTOR axis in tumor tissues.
Conclusion: CRI9 has been identified as a new inhibitor of the c-MET/PI3K/Akt/mTOR axis in HCC preclinical models.
논문정보
- Research article
- 2024년 08월 (BRIC 등록일 2024-09-02)
- 국내(교신)+국외 연구진
- 의약학 > 약학
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