Evaluation of the potential anti-cancer activity of the antidepressant sertraline in human colon cancer cell lines and in colorectal cancer-xenografted mice.
Evidence has been provided of the anti-proliferative activity of certain antidepressants, mainly the selective serotonin reuptake inhibitors (SSRIs). We tested the effect of different antidepressants on cell viability and proliferation of human colorectal carcinoma cell lines HT29 and the multi-drug resistant (MDR) LS1034. The SSRIs, paroxetine and sertraline, induced a dose-dependent inhibition of cell viability and proliferation in the two cell lines (IC50 8-15 micro M). When compared to cytotoxic agents e.g. doxorubicin, vincristine and 5-fluorouracil, the SSRIs showed comparable activity (HT29) or a superior effect (LS1034). Using flow cytometry analysis, we found that the two SSRIs arrested cells at the G0/G1 stage and stimulated DNA fragmentation in a dose-dependent manner. The SSRIs (10 and 20 microM) increased caspase-3 activation. Western blot analysis showed an increase after 24 h in c-Jun and a decrease in the expression of the anti-apoptotic protein Bcl-2. The results suggest a proapoptotic activity for the active SSRIs accompanied by mitogen-activated protein kinase cascade activation and Bcl-2 inhibition. In vivo, we used CD1 nude mice xenografted subcutaneously with HT29 cells. On day 8, after cell inoculation sertraline or paroxetine (15 mg/kg x3/week i.p.) were administered to animals (6/group), which were monitored weekly (for 5 weeks) for tumor volume and body weight. At 5 weeks, the animals survived, with no significant difference in body weight. Sertraline, though not paroxetine, significantly inhibited tumor growth. Collectively, our results suggest that the widely-used antidepressant, sertraline, possesses a potential anti-tumor activity, which circumvents the MDR mechanism. Since SSRI therapy is frequently indicated in cancer patients, the use of sertraline in colon cancer patients with co-morbidity of depression seems attractive.
Gil-Ad
Irit
I
Laboratory of Biological Psychiatry, Felsentein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University and Campus Rabin, Petah-Tikva 49100, Israel. iritgil@post.tau.ac.il
Zolokov
Amichai
A
Lomnitski
Liat
L
Taler
Michal
M
Bar
Meital
M
Luria
Drorit
D
Ram
Edward
E
Weizman
Abraham
A
D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D017374:Paroxetine; D020280:Sertraline / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000928:Antidepressive Agents; D000970:Antineoplastic Agents; D017374:Paroxetine; D020280:Sertraline