SSRI use and clinical outcomes in epithelial ovarian cancer
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Desiré K. Christensen1, Guillermo N. Armaiz-Pena2, Edgardo Ramirez1, Koji Matsuo3, Bridget Zimmerman4, Behrouz Zand5,6, Eileen Shinn7, Michael J. Goodheart8,9, David Bender8, Premal H. Thaker10, Amina Ahmed11, Frank J. Penedo12, Koen DeGeest13, Luis Mendez14, Frederick Domann15, Anil K. Sood5,6, Susan K. Lutgendorf1,8,9,16
1Department of Psychological and Brain Sciences, University of Iowa, Iowa City, Iowa, USA
2Department of Pharmacology, Ponce Health Sciences University, Ponce, Puerto Rico
3Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California, USA
4Department of Biostatistics, University of Iowa, Iowa City, Iowa, USA
5Department of Gynecologic Oncology and Reproductive Medicine, UT MD Anderson Comprehensive Cancer Center, Houston, Texas, USA
6Department of Cancer Biology, and Center for RNA Interference and Noncoding RNA, UT MD Anderson Comprehensive Cancer Center, Houston, Texas, USA
7Department of Behavioral Science, UT MD Anderson Comprehensive Cancer Center, Houston, Texas, USA
8Department of Obstetrics and Gynecology, University of Iowa, Iowa City, Iowa, USA
9Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa, USA
10Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University, St. Louis, Missouri, USA
11Department of Obstetrics and Gynecology, Lutheran General Hospital, Park Ridge, Illinois, USA
12Department of Medical Social Sciences, Northwestern University, Chicago, Illinois, USA
13Division of Gynecologic Oncology, Oregon Health and Sciences University, Portland, Oregon, USA
14Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Florida International University School of Medicine, Miami, Florida, USA
15Department of Radiation Oncology, University of Iowa, Iowa City, Iowa, USA
16Department of Urology, University of Iowa, Iowa City, Iowa, USA
Susan K. Lutgendorf, e-mail: [email protected]
Keywords: selective serotonin reuptake inhibitors, epithelial ovarian cancer, serotonin, progression, cell proliferation
Received: November 09, 2015 Accepted: April 02, 2016 Published: April 21, 2016
Selective serotonin reuptake inhibitor (SSRI) use is common among ovarian cancer patients. We examined the effect of SSRIs on survival and progression in ovarian cancer patients and effects of 5-HT on ovarian cancer cell (OCC) proliferation. Ovarian cancer patients from a 6-site study between 1994 and 2010 were included. Cox proportional hazards models were used for multivariate analysis. SSRI use was associated with decreased time to disease recurrence (HR 1.3, CI 1.0-1.6, p=0.03), but not overall survival (HR 1.1, CI 0.9-1.3, p=0.56). Compared to normal ovarian cells, most OCCs had elevated 5-HT2A receptor mRNA expression (up to 1600 fold greater expression). Clonogenic survival increased in cells treated with 10 uM (1.6 fold, p<0.001) and 20uM (1.9 fold, p=0.018) 5-HT. Mice receiving 5-HT injections had increases in tumor weight (p=0.07) and nodules (p=0.08) with increased Ki67 expression. Injections with sertraline doubled mean tumor weight in mice (p=0.16). 5-HT and sertraline both increased Ki67 expression in mouse tumors (p < 0.001).
Patients using SSRIs had significantly decreased time to disease progression. It is possible that SSRIs alter serotonin levels in the tumor microenvironment, resulting in activation of proliferation pathways. Further characterization of serotonergic pathways in ovarian cancer is recommended to demonstrate safety of these medications.
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