Desipramine Induces Apoptotic Cell Death through Nonmitochondrial and Mitochondrial Pathways in Different Types of Human Colon Carcinoma Cells

Arimochi, Hideki; Morita, Kyoji

doi:10.1159/000111144

Cited by 35 publications

(32 citation statements)

References 76 publications

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“…These findings are in agreement with previous studies which found that DMI inhibited cell proliferation and induced apoptosis in osteosarcoma cells, prostate cancer, colon cancer, renal tubular and glioma cells (14,15,(26)(27)(28)(29) and caused cell cycle arrest in colon cancer cells (13). In this study, we found a decrease in mRNA expression of Bcl-2 and survivin.…”

Section: Discussionsupporting

confidence: 94%

“…It is conceivable that DMI induces apoptosis via the mitochondrial pathway, which causes release of cytochrome c from the mitochondria to the cytoplasm which subsequently activates caspases to induce DNA fragmentation. A previous study found that DMI may cause non-oxidative apoptotic damage to different types of carcinoma cells through either a non-mitochondrial or a mitochondrial pathway, which may be related to different sensitivities of these cancer cells to this drug (13,28). Moreover, DMI caused arrest of cell cycle progression in either the G0/G1 or G2/M phase, which might be dependent upon the concentration of DMI.…”

Section: Discussionmentioning

confidence: 99%

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Effects of desipramine on the cell cycle and apoptosis in Ca3/7 mouse skin squamous carcinoma cells

Hanausek,¹

2010

Int J Mol Med

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Abstract. Desipramine (DMI) has been reported to induce glucocorticoid receptor-mediated signal transduction in recent studies. It has been suggested that a non-glucocorticoid receptor signaling pathway might play an important role in skin squamous carcinoma Ca3/7 cells. The aim of this study was to investigate the growth inhibitory effects of DMI on Ca3/7 cells by evaluating the mRNA expression of genes related to apoptosis and cell cycle progression. Hoechst nuclear staining and DNA fragmentation assays were used to detect apoptosis, and the cell cycle was analyzed by flow cytometry. Apoptotic bodies in the nuclei of cells and DNA fragmentation were observed when the Ca3/7 cells were treated with 20 μM DMI for 24 h. Quantitative RT-PCR (reverse transcriptional-polymerase chain reaction) showed that DMI caused a decrease in Bcl-2 and survivin but not Bcl-xL gene expression and an increase in the expression of Bax, Apaf-1, caspase-3 and caspase-7 in a dose-and timedependent manner. DMI also caused translocation of the apoptosis-inducing factor from the cytoplasm to the nucleus as well as cell cycle arrest in the Ca3/7 cells. Quantitative RT-PCR revealed that DMI decreased the expression of the PCNA gene and caused an increase in the expression of the p21 and p27 genes in the Ca3/7 cells. Our results showed that DMI inhibited the growth of Ca3/7 cells by inducing both apoptosis and cell cycle arrest.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Effects of desipramine on the cell cycle and apoptosis in Ca3/7 mouse skin squamous carcinoma cells

Hanausek,¹

2010

Int J Mol Med

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“…7). Interestingly, p53 levels in the presence of desipramine alone were very low—in agreement with the observation that although desipramine induces apoptosis in a mitochondrial-dependent manner, HCT116 cells are not especially sensitive to this agent [26]. All three platinum drugs induced measureable levels of p53, with oxaliplatin having the most overt effect under these conditions.…”

Section: Resultssupporting

confidence: 82%

Platinum anticancer agents and antidepressants: desipramine enhances platinum-based cytotoxicity in human colon cancer cells

et al. 2011

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A unique synergistic effect on platinum drug cytotoxicity is noted in the presence of the tricyclic anti-depressant desipramine. Desipramine is used for treating neuropathic pain, particularly in prostate cancer patients. The clinically used drugs cisplatin (cis-[PtCl2(NH3)2]), oxaliplatin [1,2-diaminocyclohexaneoxalatoplatinum(II)], and the cationic trinuclear agent BBR3464 [{trans-PtCl(NH3)2}2-μ-(trans-Pt(NH3)2(H2N(CH2)6NH2)2)]4+, which has undergone evaluation in phase II clinical trials for activity in lung and ovarian cancers, were evaluated. Surprisingly, desipramine greatly augments the cytotoxicity of all the platinum-based chemotherapeutics in HCT116 colorectal carcinoma cell lines. Desipramine enhanced cellular accumulation of cisplatin, but had no effect on the accumulation of oxaliplatin or BBR3464, suggesting that enhanced accumulation could not be a consistent means by which desipramine altered the platinum-drug-mediated cytotoxicity. The desipramine/cisplatin combination resulted in increased levels of p53 as well as mitochondrial damage, caspase activation, and poly(ADP ribose) polymerase cleavage, suggesting that desipramine may synergize with cisplatin more than with other platinum chemotherapeutics partly by activating distinct apoptotic pathways. The study argues that desipramine may be a means of enhancing chemoresponsiveness of platinum drugs and the results warrant further investigation. The results emphasize the importance of understanding the differential pharmacological action of adjuvants employed in combinations with cancer chemotherapeutics.

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“…(27) In lung cancer, TCAs induce cell death via histamine and adrenergic receptors by blocking Gα s and PKA, CREB and ATF1 signaling. (13) Additional studies have confirmed the induction of cell death by TCAs(10,28) while others found associations with reduced incidence of certain cancers. (29) Also, previous work on models of glioma showed a potential synergistic effect between chlorimipramine (a TCA) and dexamethasone,(11,30) while use of the TCA imipramine in combination with citalopram, an SSRI, induced apoptosis of acute myeloid leukemia cells.…”

Section: Discussionmentioning

confidence: 94%

Relationship between anti-depressant use and lung cancer survival

Zingone

Brown

Bowman

et al. 2017

Cancer Treatment and Research Communications

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Objectives In recent years, the anti-cancer properties of several commonly used drugs have been explored, with drugs such as aspirin and beta-blockers associated with improved cancer outcomes. Previous preclinical work demonstrated that tricyclic anti-depressants have antitumor efficacy in lung cancer. Our goal was to examine the association between anti-depressant use and survival in lung cancer. Materials and Methods We examined the association between use of common anti-depressants and survival in 1,097 lung cancer patients from the NCI-Maryland lung cancer study. The types of anti-depressants included in the study were norepinephrine and dopamine reuptake inhibitors, serotonin reuptake inhibitors, selective serotonin reuptake inhibitors, non-selective serotonin reuptake inhibitors, and tricyclic anti-depressants. Anti-depressant use was extracted from the medical history section of a detailed interviewer-administered questionnaire. Specific use in the three months before a lung cancer diagnosis was determined. Cox portioned hazards modeling was used to estimate the association between anti-depressant use with lung cancer-specific death with adjustment for potential confounding co-factors. Results Anti-depressant use was associated with extended lung cancer-specific survival. In an analysis of specific classes of anti-depressant use, NDRIs and TCAs were associated with improved survival. Importantly, the extended survival associated with anti-depressants was maintained after adjustment for the clinical indications for these drugs, suggestive of a direct effect on lung cancer biology. Conclusions Considering the manageable and largely tolerable side effects of anti-depressants, and the low cost of these drugs, these results indicate that evaluation of anti-depressants as adjunct therapeutics with chemotherapy may have a translational effect for lung cancer patients.

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Desipramine Induces Apoptotic Cell Death through Nonmitochondrial and Mitochondrial Pathways in Different Types of Human Colon Carcinoma Cells

Cited by 35 publications

References 76 publications

Effects of desipramine on the cell cycle and apoptosis in Ca3/7 mouse skin squamous carcinoma cells

Effects of desipramine on the cell cycle and apoptosis in Ca3/7 mouse skin squamous carcinoma cells

Platinum anticancer agents and antidepressants: desipramine enhances platinum-based cytotoxicity in human colon cancer cells

Relationship between anti-depressant use and lung cancer survival

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