title: JKA97, a novel benzylidene analog of harmine, exerts anti-cancer effects by inducing G1 arrest, apoptosis, and p53-independent up-regulation of p21.
abstract: JKA97, a benzylidene analog of harmine, has been found to be a promising drug candidate for human cancer therapy, although the underlying molecular mechanisms have not been fully demonstrated. In this study, we evaluated the effects of JKA97 on human breast cancer cells in vitro and in vivo. JKA97 inhibited the growth and proliferation of MCF7 (p53 wild-type), MCF7 (p53 knockdown), and MDA-MB-468 (p53 mutant) cells in a dose-dependent manner. Treatment with JKA97 arrested breast cancer cells in G1 phase and induced apoptosis. JKA97 also significantly suppressed the growth of MCF7 and MDA-MB-468 xenograft tumors. It regulated the expression levels of G1 phase regulators, such as p21, p27, cyclinE, and cylinD1. JKA97 activated p21 transcription, independent of p53, but had little effect on p21 protein stability/degradation. In summary, our results suggest that JKA97 inhibits human breast cancer cell growth through activating p21, independent of p53, which provides a basis for developing this compound as a novel drug for human breast cancer therapy.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, United States of America.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Yang
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Jiang-Jiang
authors.initials: JJ
authors.lastname: Qin
authors.forename: Ming-Hai
authors.initials: MH
authors.lastname: Wang
authors.forename: Horrick
authors.initials: H
authors.lastname: Sharma
authors.forename: John K
authors.initials: JK
authors.lastname: Buolamwini
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Ruiwen
authors.initials: R
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001597:Benzylidene Compounds / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D002243:Carbolines / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006247:Harmine / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D013343:Styrenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C528869:1-styryl-9H-pyrido(3,4-b)indole; D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; D002243:Carbolines; D050759:Cyclin-Dependent Kinase Inhibitor p21; D013343:Styrenes; D006247:Harmine