SSRI use and clinical outcomes in epithelial ovarian cancer.
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.
Department of Psychological and Brain Sciences, University of Iowa, Iowa City, Iowa, USA.
Desiré K
DK
Christensen
Department of Pharmacology, Ponce Health Sciences University, Ponce, Puerto Rico.
Guillermo N
GN
Armaiz-Pena
Department of Psychological and Brain Sciences, University of Iowa, Iowa City, Iowa, USA.
Edgardo
E
Ramirez
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California, USA.
Koji
K
Matsuo
Department of Biostatistics, University of Iowa, Iowa City, Iowa, USA.
Bridget
B
Zimmerman
Department of Gynecologic Oncology and Reproductive Medicine, UT MD Anderson Comprehensive Cancer Center, Houston, Texas, USA.|Department of Cancer Biology, and Center for RNA Interference and Noncoding RNA, UT MD Anderson Comprehensive Cancer Center, Houston, Texas, USA.
Behrouz
B
Zand
Department of Behavioral Science, UT MD Anderson Comprehensive Cancer Center, Houston, Texas, USA.
Eileen
E
Shinn
Department of Obstetrics and Gynecology, University of Iowa, Iowa City, Iowa, USA.|Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa, USA.
Michael J
MJ
Goodheart
Department of Obstetrics and Gynecology, University of Iowa, Iowa City, Iowa, USA.
David
D
Bender
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University, St. Louis, Missouri, USA.
Premal H
PH
Thaker
Department of Obstetrics and Gynecology, Lutheran General Hospital, Park Ridge, Illinois, USA.
Amina
A
Ahmed
Department of Medical Social Sciences, Northwestern University, Chicago, Illinois, USA.
Frank J
FJ
Penedo
Division of Gynecologic Oncology, Oregon Health and Sciences University, Portland, Oregon, USA.
Koen
K
DeGeest
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Florida International University School of Medicine, Miami, Florida, USA.
Luis
L
Mendez
Department of Radiation Oncology, University of Iowa, Iowa City, Iowa, USA.
Frederick
F
Domann
Department of Gynecologic Oncology and Reproductive Medicine, UT MD Anderson Comprehensive Cancer Center, Houston, Texas, USA.|Department of Cancer Biology, and Center for RNA Interference and Noncoding RNA, UT MD Anderson Comprehensive Cancer Center, Houston, Texas, USA.
Anil K
AK
Sood
Department of Psychological and Brain Sciences, University of Iowa, Iowa City, Iowa, USA.|Department of Obstetrics and Gynecology, University of Iowa, Iowa City, Iowa, USA.|Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa, USA.|Department of Urology, University of Iowa, Iowa City, Iowa, USA.
Susan K
SK
Lutgendorf
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000009:adverse effects*; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D016009:Chi-Square Distribution; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000378:metabolism; D008819:Mice, Nude; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D016017:Odds Ratio; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D016016:Proportional Hazards Models; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects*; D020280:Sertraline / Q000009:adverse effects*; D013997:Time Factors; D059016:Tumor Microenvironment; D014481:United States; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
D018687:Antidepressive Agents, Second-Generation; D019394:Ki-67 Antigen; D044402:Receptor, Serotonin, 5-HT2A; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline
cell proliferation; epithelial ovarian cancer; progression; selective serotonin reuptake inhibitors; serotonin