A Hypothesis for the Relationship between Depression and Cancer: Role of Ca2+/cAMP Signalling

Author(s): Leandro B. Bergantin*

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 20 , Issue 7 , 2020

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Graphical Abstract:


Limitations on the pharmacotherapy and a high prevalence worldwide are critical issues related to depression and cancer. It has been discussed that a dysregulation of intracellular Ca2+ homeostasis is involved in the pathogenesis of both these diseases. In addition, depression raises the risk of cancer incidence. Consistent data support the concept that depression is an independent risk issue for cancer. However, the cellular mechanisms involved in this link between depression and cancer remain uncertain. Considering our previous reports about Ca2+ and cAMP signalling pathways (Ca2+/cAMP signalling), I herein discussed the putative contribution of Ca2+/cAMP signalling in this link between depression and cancer. Moreover, it is important to take depression into account during the process of prevention and treatment of cancer.

Keywords: Depression, cancer, Ca2+/cAMP signaling, homeostasis, pharmacotherapy, homeostasis.

Jia, Y.; Li, F.; Liu, Y.F.; Zhao, J.P.; Leng, M.M.; Chen, L. Depression and cancer risk: a systematic review and meta-analysis. Public Health, 2017, 149, 138-148.
[http://dx.doi.org/10.1016/j.puhe.2017.04.026] [PMID: 28641155]
Bergantin, L.B. Hypertension, diabetes and neurodegenerative diseases: Is there a clinical link through the Ca2+/cAMP signalling interaction? Curr. Hypertens. Rev., 2019, 15(1), 32-39.
[http://dx.doi.org/10.2174/1573402114666180817113242] [PMID: 30117399]
Bergantin, L.B.; Caricati-Neto, A. Challenges for the pharmacological treatment of neurological and psychiatric disorders: Implications of the Ca(2+)/cAMP intracellular signalling interaction. Eur. J. Pharmacol., 2016, 788, 255-260.
[http://dx.doi.org/10.1016/j.ejphar.2016.06.034] [PMID: 27349146]
Bergantin, L.B.; Caricati-Neto, A. Advances for the pharmacotherapy of depression - Presenting the rising star: Ca2+/camp signaling interaction. J. Syst. Integr. Neurosci., 2017, 3
Bergantin, L.B. Cancer and hypertension: Debating the clinical link through the Ca2+/cAMP signaling. Glob. Vaccines Immunol., 2018, 3
Tully, P.J.; Peters, R.; Pérès, K.; Anstey, K.J.; Tzourio, C. Effect of SSRI and calcium channel blockers on depression symptoms and cognitive function in elderly persons treated for hypertension: three city cohort study. Int. Psychogeriatr., 2018, 30(9), 1345-1354.
[http://dx.doi.org/10.1017/S1041610217002903] [PMID: 29559030]
Bergantin, L.B.; Souza, C.F.; Ferreira, R.M.; Smaili, S.S.; Jurkiewicz, N.H.; Caricati-Neto, A.; Jurkiewicz, A. Novel model for “calcium paradox” in sympathetic transmission of smooth muscles: role of cyclic AMP pathway. Cell Calcium, 2013, 54(3), 202-212.
[http://dx.doi.org/10.1016/j.ceca.2013.06.004] [PMID: 23849429]
Sommer, N.; Löschmann, P.A.; Northoff, G.H.; Weller, M.; Steinbrecher, A.; Steinbach, J.P.; Lichtenfels, R.; Meyermann, R.; Riethmüller, A.; Fontana, A. The antidepressant rolipram suppresses cytokine production and prevents autoimmune encephalomyelitis. Nat. Med., 1995, 1(3), 244-248.
[http://dx.doi.org/10.1038/nm0395-244] [PMID: 7585041]
Xiao, L.; O’Callaghan, J.P.; O’Donnell, J.M. Effects of repeated treatment with phosphodiesterase-4 inhibitors on cAMP signaling, hippocampal cell proliferation, and behavior in the forced-swim test. J. Pharmacol. Exp. Ther., 2011, 338(2), 641-647.
[http://dx.doi.org/10.1124/jpet.111.179358] [PMID: 21566211]
Douglas, W.W.; Rubin, R.P. The role of calcium in the secretory response of the adrenal medulla to acetylcholine. J. Physiol., 1961, 159, 40-57.
[http://dx.doi.org/10.1113/jphysiol.1961.sp006791] [PMID: 13887557]
Baker, P.F.; Knight, D.E. Calcium-dependent exocytosis in bovine adrenal medullary cells with leaky plasma membranes. Nature, 1978, 276(5688), 620-622.
[http://dx.doi.org/10.1038/276620a0] [PMID: 723944]
Kreye, V.A.; Lüth, J.B. Proceedings: Verapamil-induced phasic contractions of the isolated rat vas deferens. Naunyn Schmiedebergs Arch. Pharmacol., 1975, 287(Suppl.), R43.
[PMID: 1143442]
French, A.M.; Scott, N.C. A comparison of the effects of nifedipine and verapamil on rat vas deferens. Br. J. Pharmacol., 1981, 73(2), 321-323.
[http://dx.doi.org/10.1111/j.1476-5381.1981.tb10424.x] [PMID: 7236986]
Moritoki, H.; Iwamoto, T.; Kanaya, J.; Maeshiba, Y.; Ishida, Y.; Fukuda, H. Verapamil enhances the non-adrenergic twitch response of rat vas deferens. Eur. J. Pharmacol., 1987, 140(1), 75-83.
[http://dx.doi.org/10.1016/0014-2999(87)90636-4] [PMID: 3113986]
Caricati-Neto, A.; García, A.G.; Bergantin, L.B. Pharmacological implications of the Ca(2+)/cAMP signaling interaction: from risk for antihypertensive therapy to potential beneficial for neurological and psychiatric disorders. Pharmacol. Res. Perspect., 2015, 3(5), e00181
[http://dx.doi.org/10.1002/prp2.181] [PMID: 26516591]
Larkman, A.U.; Jack, J.J. Synaptic plasticity: hippocampal LTP. Curr. Opin. Neurobiol., 1995, 5(3), 324-334.
[http://dx.doi.org/10.1016/0959-4388(95)80045-X] [PMID: 7580155]
Nicoll, R.A.; Malenka, R.C. Contrasting properties of two forms of long-term potentiation in the hippocampus. Nature, 1995, 377(6545), 115-118.
[http://dx.doi.org/10.1038/377115a0] [PMID: 7675078]
Duman, R.S. Depression: a case of neuronal life and death? Biol. Psychiatry, 2004, 56(3), 140-145.
[http://dx.doi.org/10.1016/j.biopsych.2004.02.033] [PMID: 15271581]
Gomez-Ospina, N.; Tsuruta, F.; Barreto-Chang, O.; Hu, L.; Dolmetsch, R. The C terminus of the L-type voltage-gated calcium channel Ca(V)1.2 encodes a transcription factor. Cell, 2006, 127(3), 591-606.
[http://dx.doi.org/10.1016/j.cell.2006.10.017] [PMID: 17081980]
Kale, V.P.; Amin, S.G.; Pandey, M.K. Targeting ion channels for cancer therapy by repurposing the approved drugs. Biochim. Biophys. Acta, 2015, 1848(10 Pt B), 2747-2755.
[http://dx.doi.org/10.1016/j.bbamem.2015.03.034] [PMID: 25843679]
Dziegielewska, B.; Gray, L.S.; Dziegielewski, J. T-type calcium channels blockers as new tools in cancer therapies. Pflugers Arch., 2014, 466(4), 801-810.
[http://dx.doi.org/10.1007/s00424-014-1444-z] [PMID: 24449277]
Ohkubo, T.; Yamazaki, J. T-type voltage-activated calcium channel Cav3.1, but not Cav3.2, is involved in the inhibition of proliferation and apoptosis in MCF-7 human breast cancer cells. Int. J. Oncol., 2012, 41(1), 267-275.
[http://dx.doi.org/10.3892/ijo.2012.1422] [PMID: 22469755]
Gackière, F.; Bidaux, G.; Delcourt, P.; Van Coppenolle, F.; Katsogiannou, M.; Dewailly, E.; Bavencoffe, A.; Van Chuoï-Mariot, M.T.; Mauroy, B.; Prevarskaya, N.; Mariot, P. CaV3.2 T-type calcium channels are involved in calcium-dependent secretion of neuroendocrine prostate cancer cells. J. Biol. Chem., 2008, 283(15), 10162-10173.
[http://dx.doi.org/10.1074/jbc.M707159200] [PMID: 18230611]
Latour, I.; Louw, D.F.; Beedle, A.M.; Hamid, J.; Sutherland, G.R.; Zamponi, G.W. Expression of T-type calcium channel splice variants in human glioma. Glia, 2004, 48(2), 112-119.
[http://dx.doi.org/10.1002/glia.20063] [PMID: 15378657]
Kim, K.H.; Kim, D.; Park, J.Y.; Jung, H.J.; Cho, Y.H.; Kim, H.K.; Han, J.; Choi, K.Y.; Kwon, H.J. NNC 55-0396, a T-type Ca2+ channel inhibitor, inhibits angiogenesis via suppression of hypoxia-inducible factor-1α signal transduction. J. Mol. Med. (Berl.), 2015, 93(5), 499-509.
[http://dx.doi.org/10.1007/s00109-014-1235-1] [PMID: 25471482]
Yoshida, J.; Ishibashi, T.; Nishio, M. G1 cell cycle arrest by amlodipine, a dihydropyridine Ca2+ channel blocker, in human epidermoid carcinoma A431 cells. Biochem. Pharmacol., 2007, 73(7), 943-953.
[http://dx.doi.org/10.1016/j.bcp.2006.12.011] [PMID: 17217918]
Krouse, A.J.; Gray, L.; Macdonald, T.; McCray, J. Repurposing and rescuing of mibefradil, an antihypertensive, for cancer: A case study. Assay Drug Dev. Technol., 2015, 13(10), 650-653.
[http://dx.doi.org/10.1089/adt.2015.29014.ajkdrrr] [PMID: 26690767]
Murray, F.; Insel, P.A. Targeting cAMP in chronic lymphocytic leukemia: a pathway-dependent approach for the treatment of leukemia and lymphoma. Expert Opin. Ther. Targets, 2013, 17(8), 937-949.
[http://dx.doi.org/10.1517/14728222.2013.798304] [PMID: 23647244]
Fajardo, A.M.; Piazza, G.A.; Tinsley, H.N. The role of cyclic nucleotide signaling pathways in cancer: targets for prevention and treatment. Cancers (Basel), 2014, 6(1), 436-458.
Drees, M.; Zimmermann, R.; Eisenbrand, G. 3′,5′-Cyclic nucleotide phosphodiesterase in tumor cells as potential target for tumor growth inhibition. Cancer Res., 1993, 53(13), 3058-3061.
[PMID: 8391385]
Bergantin, L.B.; Caricati-Neto, A. Emerging concepts for neuroscience field from Ca2+/cAMP signalling interaction. J. Neurol. Exp. Neurosci., 2017, 3(1), 29-32.
Fujita, M.; Richards, E.M. cAMP signaling in brain is decreased in unmedicated depressed patients and increased by treatment with a selective serotonin reuptake inhibitor. Mol. Psychiatry, 2017, 22(5), 754-759.
Caricati-Neto, A.; Bergantin, L.B. Pharmacological modulation of neural Ca2+/camp signaling interaction as therapeutic goal for treatment of Alzheimer’s disease. J. Syst. Integr. Neurosci., 2017, 3
Caricati-Neto, A.; Bergantin, L.B. The passion of a scientific discovery: The “calcium paradox” due to Ca2+/camp interaction. J. Syst. Integr. Neurosci., 2017, 3
Caricati-Neto, A.; Bergantin, L.B. From a “eureka insight” to a novel potential therapeutic target to treat Parkinson’s disease: The Ca2+/camp signalling interaction. J. Syst. Integr. Neurosci., 2017, 4
Bergantin, L.B. Debating the “bidirectional link” between diabetes and depression through the Ca2+/cAMP signalling: Off-label effects of Ca2+ channel blockers. Pharmacol. Res., 2019, 141, 298-302.
[http://dx.doi.org/10.1016/j.phrs.2019.01.008] [PMID: 30639385]
Bergantin, L.B.; Caricati-Neto, A. The “Calcium Paradox” and its Impact on Neurological and Psychiatric Diseases; Cambridge Scholars Publishing: UK, 2018.
Bergantin, L.B. Diabetes and cancer: Debating the link through Ca2+/cAMP signalling. Cancer Lett., 2019, 448, 128-131.
Marques, R.; Peres, C.G.; Vaz, C.V.; Gomes, I.M.; Figueira, M.I.; Cairrão, E.; Verde, I.; Maia, C.J.; Socorro, S. 5α-Dihydrotestosterone regulates the expression of L-type calcium channels and calcium-binding protein regucalcin in human breast cancer cells with suppression of cell growth. Med. Oncol., 2015, 32(9), 228.
[http://dx.doi.org/10.1007/s12032-015-0676-x] [PMID: 26255063]
Vaz, C.V.; Rodrigues, D.B.; Socorro, S.; Maia, C.J. Effect of extracellular calcium on regucalcin expression and cell viability in neoplastic and non-neoplastic human prostate cells. Biochim. Biophys. Acta, 2015, 1853(10 Pt A), 2621-2628.
[http://dx.doi.org/10.1016/j.bbamcr.2015.07.006] [PMID: 26171977]
Yamaguchi, M.; Osuka, S.; Shoji, M.; Weitzmann, M.N.; Murata, T. Survival of lung cancer patients is prolonged with higher regucalcin gene expression: suppressed proliferation of lung adenocarcinoma A549 cells in vitro. Mol. Cell. Biochem., 2017, 430(1-2), 37-46.
[http://dx.doi.org/10.1007/s11010-017-2952-x] [PMID: 28181135]
Yamaguchi, M. Suppressive role of regucalcin in liver cell proliferation: involvement in carcinogenesis. Cell Prolif., 2013, 46(3), 243-253.
Huang, M.Y.; Wang, H.M.; Chang, H.J.; Hsiao, C.P.; Wang, J.Y.; Lin, S.R. Overexpression of S100B, TM4SF4, and OLFM4 genes is correlated with liver metastasis in Taiwanese colorectal cancer patients. DNA Cell Biol., 2012, 31(1), 43-49.
[http://dx.doi.org/10.1089/dna.2011.1264] [PMID: 22011044]
Cho, Y.W.; Kim, E.J.; Nyiramana, M.M.; Shin, E.J.; Jin, H.; Ryu, J.H.; Kang, K.R.; Lee, G.W.; Kim, H.J.; Han, J.; Kang, D. Paroxetine induces apoptosis of human breast cancer MCF-7 cells through Ca2+-and p38 MAP kinase-dependent ROS generation. Cancers (Basel), 2019, 11(1), E64
[http://dx.doi.org/10.3390/cancers11010064] [PMID: 30634506]
Radin, D.P.; Patel, P. A current perspective on the oncopreventive and oncolytic properties of selective serotonin reuptake inhibitors. Biomed. Pharmacother., 2017, 87, 636-639.
[http://dx.doi.org/10.1016/j.biopha.2017.01.024] [PMID: 28088112]
Bortolato, B.; Hyphantis, T.N.; Valpione, S.; Perini, G.; Maes, M.; Morris, G.; Kubera, M.; Köhler, C.A.; Fernandes, B.S.; Stubbs, B.; Pavlidis, N.; Carvalho, A.F. Depression in cancer: The many biobehavioral pathways driving tumor progression. Cancer Treat. Rev., 2017, 52, 58-70.
[http://dx.doi.org/10.1016/j.ctrv.2016.11.004] [PMID: 27894012]
Caruso, R.; Nanni, M.G.; Riba, M.; Sabato, S.; Mitchell, A.J.; Croce, E.; Grassi, L. Depressive spectrum disorders in cancer: prevalence, risk factors and screening for depression: a critical review. Acta Oncol., 2017, 56(2), 146-155.
[http://dx.doi.org/10.1080/0284186X.2016.1266090] [PMID: 28140731]
Parker, G.; Brotchie, H. Pancreatic cancer and depression: A narrative review. J. Nerv. Ment. Dis., 2017, 205(6), 487-490.
[http://dx.doi.org/10.1097/NMD.0000000000000593] [PMID: 28557883]
Chen, C.Y.; Yang, Y.H.; Lee, C.P.; Wang, T.Y.; Cheng, B.H.; Huang, Y.C.; Chen, P.C.; Liang, S.H.; Dewey, M.; Chen, V.C. Risk of depression following uterine cancer: A nationwide population-based study. Psychooncology, 2017, 26(11), 1770-1776.
[http://dx.doi.org/10.1002/pon.4360] [PMID: 28029721]
Kolva, E.; Hoffecker, L.; Cox-Martin, E. Suicidal ideation in patients with cancer: A systematic review of prevalence, risk factors, intervention and assessment. Palliat. Support. Care, 2019, 26, 1-14.
[http://dx.doi.org/10.1017/S1478951519000610] [PMID: 31554521]
Wang, B.; Li, B.; Tan, S.; Zhai, J.; Chen, M. Risk factors for anxiety and depression in Chinese patients undergoing surgery for endometrial cancer. Can. J. Physiol. Pharmacol., 2020, 98(1), 1-5.
[http://dx.doi.org/10.1139/cjpp-2019-0302] [PMID: 31518506]
Yan, X.R.; Chen, X.; Zhang, P. Prevalence and risk factors of depression in patients with lung cancer: protocol for a systematic review and meta-analysis. BMJ Open, 2019, 9(8), e028994
[http://dx.doi.org/10.1136/bmjopen-2019-028994] [PMID: 31473615]

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Year: 2020
Page: [777 - 782]
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DOI: 10.2174/1871520620666200220113817
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