title: p28-Mediated Activation of p53 in G2-M Phase of the Cell Cycle Enhances the Efficacy of DNA Damaging and Antimitotic Chemotherapy.
abstract: p28 is an anionic cell-penetrating peptide of 28 amino acids that activates wild-type and mutated p53, leading subsequently to selective inhibition of CDK2 and cyclin A expression and G2-M cell-cycle arrest. In this study, we investigated the cytotoxic effects of p28 treatment alone and in combination with DNA-damaging and antimitotic agents on human cancer cells. p28 enhanced the cytotoxic activity of lower concentrations (IC20-50) of DNA-damaging drugs (doxorubicin, dacarbazine, temozolamide) or antimitotic drugs (paclitaxel and docetaxel) in a variety of cancer cells expressing wild-type or mutated p53. Mechanistic investigations revealed that p28 induced a post-translational increase in the expression of wild-type or mutant p53 and p21, resulting in cell-cycle inhibition at the G2-M phase. The enhanced activity of these anticancer agents in combination with p28 was facilitated through the p53/p21/CDK2 pathway. Taken together, these results highlight a new approach to maximize the efficacy of chemotherapeutic agents while reducing dose-related toxicity. Cancer Res; 76(8); 2354-65. ©2016 AACR.
authors.affiliation: Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago College of Medicine, Chicago, Illinois. tohru@uic.edu.
authors.forename: Tohru
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago College of Medicine, Chicago, Illinois.
authors.forename: Tapas K
authors.initials: TK
authors.lastname: Das Gupta
authors.affiliation: Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago College of Medicine, Chicago, Illinois.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Beattie
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000502:physiology*; D004249:DNA Damage; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D016195:G2 Phase; D064593:Heterografts; D008297:Male; D008819:Mice, Nude; D000077204:Temozolomide; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D057846:Cell-Penetrating Peptides; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003606:Dacarbazine; D000077204:Temozolomide