Table 1.

Summary of the main findings described in this review concerning the anticancer effects of sertraline. [+] and [-] indicate existence or absence of in vivo studies, respectively.

Condition	Cell Lines	In Vivo Results?	Main Findings	References
Lung cancer	A549, H522, PC9/R, and H1975	+	Sertraline is able to significantly decrease the viability of different TKI-resistant NSCLC cell lines. The combined treatment of sertraline with erlotinib effectively promotes autophagy. The combined treatment with sertraline and erlotinib affects the regulation of the AMPK/mTOR signaling pathway. The combination of sertraline and erlotinib is able to successfully decrease tumor growth and increase mouse survival.	[40]
	A549, HCC-15, and Calu-3	-	Sertraline induces TRAIL-mediated apoptosis by downregulation of AMP-activated protein kinase phosphorylation, which results in the inhibition of autophagic flux and upregulation of death receptor 5 expression, which leads to activation of the apoptotic caspase cascade.	[41]
Colorectal cancer	HCT116	+	Sertraline interferes with the TCTP-P53 feedback loop, by increasing the expression of P53 and decreasing the expression of TCTP, promoting P53-dependent apoptosis of cancer cells. This drug also affects the self-renewal of cancer stem cells, as demonstrated by the reduction in the mammosphere-forming efficiency of primary mammary tumor cells from ErbB2 transgenic mice.	[43]
	HT-29 and LS1034	+	Sertraline was able to significantly reduce cell viability and proliferation in a dose-dependent manner. Sertraline treatment in HT-29 cells caused cell cycle arrest at G0/G1 and induced DNA fragmentation in a dose-dependent manner. Sertraline treatment enhanced caspase-3 activation and increased c-Jun expression, causing a decrease in the expression of the anti-apoptotic protein Bcl-2, suggesting that sertraline may induce cell apoptosis through MAPK cascade activation and Bcl-2 inhibition. Sertraline is able to significantly inhibit tumor growth after 5 weeks of treatment.	[46]
	HT-29	-	The combination of 5-fluorouracil with sertraline resulted in enhanced significant toxicity compared to 5-fluorouracil alone.	[47]
	HT-29	-	Sertraline, both alone and combined with 5-fluorouracil can induce an epithelial-mesenchymal transition reversal.	[50]
	HT-29	-	The combination of sertraline with honeybee venom produced better anti-cancer efficacy than each drug alone, supporting the use of sertraline in adjuvant strategies.	[51]
	SW480 and HCT116	+	Inhibiting SERT with sertraline promotes the uptake and catabolism of extracellular tryptophan in colon cancer, both in vitro and in vivo. Tryptophan uptake blockage can sensitize colon cancer cells to SSRIs such as sertraline.	[52]
Breast cancer	MCF-7	+	Sertraline significantly reduces cell viability, proliferation, and protein synthesis in a concentration-dependent manner. Sertraline reduces polysome content and increases 80S ribosomes. Sertraline-induced inhibition in translation is related to a decrease in the eukaryotic initiation factor (eIF) 4F complex levels, altered localization of eIF4E, and increased eIF2α phosphorylation that leads to an increase in REDD1 expression, affecting the mTOR pathway. Sertraline increases chemosensitivity to doxorubicin in a murine lymphoma model.	[54]
	MCF-7	-	Sertraline is cytotoxic against this cell line with an IC50 of 16 µM. Sertraline induced apoptosis in these cells, phosphatidylserine externalization, and PARP cleavage.	[55]
	BTIC	+	Sertraline affects breast tumor-initiating cells activity in a dose-dependent manner, by reducing the frequency of sphere-forming cells. Exposure of breast tumor cells ex vivo to sertraline induces a reduction in breast tumor-initiating cells frequency, decreases the growth rate of tumor allografts, and reduces their volume in a dose-dependent manner. The combination of sertraline with docetaxel induces a reduction in tumor cell proliferation and causes cell death in mammary tumor allografts, in a synergistic way.	[56,57]
	MDA-MB-231, MDA-MB-468, MCF-7 and HCC70	+	Sertraline inhibits the serine/glycine synthesis enzyme serine hydroxymethyltransferase. In combination with artemether, sertraline displayed an enhanced antiproliferative effect, caused by G1-S cell cycle arrest. This combination resulted in serine-selective antitumor activity in breast cancer mouse xenografts.	[58]
	MCF-7	-	Sertraline alone demonstrated the ability to significantly reduce cell viability, causing more than 70% of cell death, and with an IC50 of 2.22 µM. When combined with paclitaxel, sertraline was not able to significantly increase the cytotoxic effect of the antineoplastic drug. The combination of sertraline with doxorubicin demonstrated that the use of sertraline as an adjuvant agent is not advantageous.	[47,50]
	MCF-7	-	Sertraline significantly inhibits the growth of these cells, at concentrations above 10 µM. The combination of sertraline and honeybee venom demonstrated more significant anticancer efficacy than both drugs alone, with more than 50% cell death.	[51]
Hepatocellular cancer	HepG2	-	Sertraline is able to decrease cell viability and induce apoptosis in a time and dose-dependent manner. Sertraline activates the intrinsic checkpoint protein caspase-9, inducing the release of cytochrome c from mitochondria to cytosol, in a process Bcl-2-dependent. Sertraline induces apoptosis by intrinsic and extrinsic pathways. Sertraline causes programmed cell death by increasing the expression of tumor necrosis factor (TNF) as well as the phosphorylation of JNK, ERK1/2, and p38.	[59]
	HepG2	-	Sertraline was able to significantly decrease the viability of these tumor cells, with an IC50 of 1.24 µM. The exposure to 2 µM sertraline caused a significant increase in the caspase-3/7 activity.	[60]
Leukemia	Jurkat T cell	-	The IC50 value of 9.5 µM for sertraline, with less than 40% of viable cells in concentrations above 15 µM. Sertraline significantly reduces cell viability to a higher degree than vincristine and cyclophosphamide. Sertraline is able to decrease the number of proliferative cells. Sertraline increases the expression of caspase-3 and decreases the expression of Bcl-2. The combination of sertraline with vincristine and doxorubicin resulted in improvements in the anticancer effects.	[61]
	NB4, NB4-R1 and NB4-R2	+	Sertraline has significant anticancer activity. Sertraline exerts cell death by apoptosis and autophagy. Autophagy inhibition leads to a reduction in sertraline-induced apoptosis and cell growth inhibition.	[62]
Brain cancer	U87	-	Sertraline alone is able to decrease cell content in a dose-dependent manner. The combination of imatinib plus sertraline resulted in synergistic interactions. A significant reduction in the expression of pAKT was detected after treatment of imatinib + sertraline, suggesting that the downregulation of pAKT may be involved in the synergist anticancer effect between imatinib and sertraline.	[63]
Melanoma	A375	+	Sertraline can effectively reduce cell viability in a dose-dependent manner. Sertraline can effectively target Akt and inhibit its phosphorylation, inducing cell death through the induction of the endoplasmic reticulum. In vivo studies in A375 xenografts demonstrated that sertraline is able to reduce tumor growth.	[64]
	MeWo, A2058, and B16-F10	+	Treatment with sertraline leads to the inhibition of TCTP causing a decrease in cell viability, reduced migration properties, and a diminished ability of cells to form colonies. Sertraline was able to significantly reduce tumor growth to a higher degree than dacarbazine.	[65]
Oral cancer	OC2	-	Sertraline causes an increase in cytosolic free Ca2+ levels, in a concentration-dependent manner. Sertraline induces an increase in cytosolic free Ca2+ levels by causing phospholipase C-independent Ca2+ release from the endoplasmic reticulum and by Ca2+ influx via store-operated Ca2+ channels.	[66]
Ovarian cancer	OVCAR-8 and NCI/ADR-Res (NAR)	+	Sertraline is able to modulate efflux pumps in cellular models of multidrug resistance. In vivo results demonstrated that the combination of sertraline with Doxil® is efficient in reducing tumor growth and progression as well as extending the survival of tumor-bearing mice.	[67]
Prostate cancer	PC-3	-	Sertraline induces an increase in cytosolic free Ca2+ levels, in a concentration-dependent manner. Sertraline induces phospholipase C-dependent release of Ca2+ from the endoplasmic reticulum and from multiple Ca2+ influx pathways involving the store-operated Ca2+ channels. Sertraline was also able to induce apoptosis in a concentration-dependent manner, independent of Ca2+ rise.	[68]
	PCSC	-	Sertraline efficiently inhibits tumorigenesis, angiogenesis and decreases the metastatic potential of prostate cancer stem cells. Sertraline induces both apoptosis and autophagy by the generation of free ROS, hydrogen peroxide formation, lipid peroxidation, and depletion of the levels of glutathione. Sertraline causes G0 arrest in prostate cancer stem cells. Sertraline downregulates the expression levels of aldehyde dehydrogenase 1 and cluster of differentiation 44 (CD44) stem cell markers. Sertraline decreases the levels of TCTP, phospho TCTP, survivin, and cellular inhibitor of apoptosis protein 1; on the other side, this drug significantly increases the levels of cleaved caspase 3 and cleaved Poly [ADP-ribose] polymerase 1. Sertraline affects the expression of stem cells, epithelial–mesenchymal transition, and autophagy markers.	[69]
Gastric cancer	SGC-7901/DDP	-	Sertraline reduces the proliferation of this cell line. Sertraline and its derivatives induced cell death by apoptosis and cell cycle arrest and targeted the PI3K/Akt/mTOR signaling pathway.	[70]
Osteosarcoma	MG63	-	Sertraline increases cytosolic free Ca2+ levels, in a concentration-dependent manner. Sertraline induces phospholipase C-dependent release of Ca2+ from the endoplasmic reticulum and Ca2+ entry by L-type Ca2+ channels and store-operated Ca2+ channels. Sertraline induces apoptosis in a concentration-dependent manner. Treatment with sertraline also leads to an increase in the levels of ROS, suggesting that cell death by apoptosis may involve the mitochondrial pathway.	[71]