title: Purvalanol A is a strong apoptotic inducer via activating polyamine catabolic pathway in MCF-7 estrogen receptor positive breast cancer cells.
abstract: Purvalanol A is a specific CDK inhibitor which triggers apoptosis by causing cell cycle arrest in cancer cells. Although it has strong apoptotic potential, the mechanistic action of Purvalanol A on significant cell signaling targets has not been clarified yet. Polyamines are crucial metabolic regulators affected by CDK inhibition because of their role in cell cycle progress as well. In addition, malignant cells possess impaired polyamine homeostasis with high level of intracellular polyamines. Especially induction of polyamine catabolic enzymes spermidine/spermine N1-acetyltransferase (SSAT), polyamine oxidase (PAO) and spermine oxidase (SMO) induced toxic by-products in correlation with the induction of apoptosis in cancer cells. In this study, we showed that Purvalanol A induced apoptosis in caspase- dependent manner in MCF-7 ER(+) cells, while MDA-MB-231 (ER-) cells were less sensitive against drug. In addition Bcl-2 is a critical target for Purvalanol A, since Bcl-2 overexpressed cells are more resistant to Purvalanol A-mediated apoptosis. Furthermore, exposure of MCF-7 cells to Purvalanol A triggered SSAT and PAO upregulation and the presence of PAO/SMO inhibitor, MDL 72,527 prevented Purvalanol A-induced apoptosis.
authors.affiliation: Molecular Biology and Genetics Department, Science and Literature Faculty, Istanbul Kultur University, Atakoy Campus, 34156, Istanbul, Turkey.
authors.forename: Pınar
authors.initials: P
authors.lastname: Obakan
authors.forename: Elif Damla
authors.initials: ED
authors.lastname: Arısan
authors.forename: Pelin
authors.initials: P
authors.lastname: Özfiliz
authors.forename: Ajda
authors.initials: A
authors.lastname: Çoker-Gürkan
authors.forename: Narçin
authors.initials: N
authors.lastname: Palavan-Ünsal
mesh_terms: D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D053858:Metabolic Networks and Pathways; D008928:Mitochondria / Q000187:drug effects; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism; D011687:Purines / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D000097667:Polyamine Oxidase; D000099228:Diamine N-Acetyltransferase
chemical_list: D000123:Acetyltransferases; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011073:Polyamines; D011687:Purines; D011960:Receptors, Estrogen; D000097667:Polyamine Oxidase; D000099228:Diamine N-Acetyltransferase; C471843:6-((3-chloro)anilino)-2-(isopropyl-2-hydroxyethylamino)-9-isopropylpurine