title: Adapalene inhibits the activity of cyclin-dependent kinase 2 in colorectal carcinoma.
abstract: Cyclin-dependent kinase 2 (CDK2) has been reported to be overexpressed in human colorectal cancer; it is responsible for the G1‑to‑S‑phase transition in the cell cycle and its deregulation is a hallmark of cancer. The present study was the first to use idock, a free and open‑source protein‑ligand docking software developed by our group, to identify potential CDK2 inhibitors from 4,311 US Food and Drug Administration‑approved small molecular drugs with a re‑purposing strategy. Among the top compounds identified by idock score, nine were selected for further study. Among them, adapalene (ADA; CD271,6‑[3‑(1‑adamantyl)‑4‑methoxyphenyl]‑2‑naphtoic acid) exhibited the highest anti‑proliferative effects in LOVO and DLD1 human colon cancer cell lines. Consistent with the expected properties of CDK2 inhibitors, the present study demonstrated that ADA significantly increased the G1‑phase population and decreased the expression of CDK2, cyclin E and retinoblastoma protein (Rb), as well as the phosphorylation of CDK2 (on Thr‑160) and Rb (on Ser‑795). Furthermore, the anti‑cancer effects of ADA were examined in vivo on xenograft tumors derived from DLD1 human colorectal cancer cells subcutaneously inoculated in BALB/C nude mice. ADA (20 mg/kg orally) exhibited marked anti‑tumor activity, comparable to that of oxaliplatin (40 mg/kg), and dose‑dependently inhibited tumor growth (P<0.05), while combined administration of ADA and oxaliplatin produced the highest therapeutic effect. To the best of our knowledge, the present study was the first to indicate that ADA inhibits CDK2 and is a potential candidate drug for the treatment of human colorectal cancer.
authors.affiliation: Biotechnology Center, Kunming Medical University, Kunming, Yunnan 650000, P.R. China.
authors.forename: Xi-Nan
authors.initials: XN
authors.lastname: Shi
authors.affiliation: Department of Computer Science and Engineering, Chinese University of Hong Kong, Hong Kong 999077, P.R. China.
authors.forename: Hongjian
authors.initials: H
authors.lastname: Li
authors.affiliation: The Cancer Biotherapy Institute of Jiangsu, Xuzhou Medical College, Xuzhou, Jiangsu 221000, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yao
authors.affiliation: Biotechnology Center, Kunming Medical University, Kunming, Yunnan 650000, P.R. China.
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Biotechnology Center, Kunming Medical University, Kunming, Yunnan 650000, P.R. China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Computer Science and Engineering, Chinese University of Hong Kong, Hong Kong 999077, P.R. China.
authors.forename: Kwong-Sak
authors.initials: KS
authors.lastname: Leung
authors.affiliation: Biotechnology Center, Kunming Medical University, Kunming, Yunnan 650000, P.R. China.
authors.forename: Hsiang-Fu
authors.initials: HF
authors.lastname: Kung
authors.affiliation: Biotechnology Center, Kunming Medical University, Kunming, Yunnan 650000, P.R. China.
authors.forename: Marie Chia-Mi
authors.initials: MC
authors.lastname: Lin
mesh_terms: D000068816:Adapalene / Q000737:chemistry / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D019927:Cyclin E / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004338:Drug Combinations; D005260:Female; D015870:Gene Expression; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010766:Phosphorylation / Q000187:drug effects; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019927:Cyclin E; D004338:Drug Combinations; D009944:Organoplatinum Compounds; D016160:Retinoblastoma Protein; D000077150:Oxaliplatin; D000068816:Adapalene; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2