title: A chemotherapy-associated senescence bystander effect in breast cancer cells.
abstract: A bystander effect typically refers to the death, altered growth or damage of cells that have not directly received chemotherapy or irradiation. Cancer cells derived from solid tumors readily undergo senescence in response to chemotherapeutic agents, prompting us to test for the existence of a senescence bystander effect. MCF-7 breast cancer cells were acutely exposed to Adriamycin to trigger senescence. Naïve MCF-7 cells, when cultured in conditioned media from senescent breast cancer cells, growth arrested despite mitogenic stimulation and exhibited SA-beta-galactosidase activity, an enlarged cell size and stable upregulation of p21(WAF1) protein, collectively indicating a senescent state. In contrast, HCT-116 colon cancer cells, which also undergo p53-mediated senescence in response to acute AdR, did not undergo growth inhibition or senescence when cultured with conditioned media from senescent HCT-116 cells. Reciprocal experiments indicated that naïve HCT-116 cells, like MCF-7 cells, are susceptible to the growth inhibitory effects of a breast cancer-derived mediator, which is independent of residual drug in conditioned media. Our study reveals a novel action of Adriamycin, which may contribute to its potent anti-breast cancer activity and lead to the discovery of additional therapeutic targets for the exploitation of a senescence bystander effect.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Di
authors.forename: Andrew Taylor
authors.initials: AT
authors.lastname: Bright
authors.forename: Ricardo
authors.initials: R
authors.lastname: Bellott
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gaskins
authors.forename: Jacques
authors.initials: J
authors.lastname: Robert
authors.forename: Shawn
authors.initials: S
authors.lastname: Holt
authors.forename: David
authors.initials: D
authors.lastname: Gewirtz
authors.forename: Lynne
authors.initials: L
authors.lastname: Elmore
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D024201:Bystander Effect / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D002851:Chromatography, High Pressure Liquid; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006801:Humans; D008954:Models, Biological; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin