The Anti-Cancer Properties Of Antidepressants: A Bibliography

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Antidepressants are known to have analgesic and antiemetic properties, as well as the ability to remit hot flashes induced by chemotherapy. Their anticancer properties, however, are not widely appreciated. In this review I have assembled a bibliography in which antidepressants kill cancer cells, inhibit their proliferation, reverse multidrug resistance, protect nonmalignant human cells from radiation and chemotherapy toxicity, and target the mitochondria of cancer cells while sparing those of health ones.

Evidence based, translational, and transformational, are the standards for optimal treatment. The forty eight studies listed below fulfill all, and other articles may be retrieved by entering “antidepressants” and “cancer” into Medline. Epidemiological studies have shown that depression predisposes to cancer, and accelerates and increases its mortality. Nonetheless, vested interests by the thousands have suppressed the paradigm shift. Unless widely disseminated to physicians, patients, and the public, so as to bypass vested interests, paradigm shifts cannot become medical revolutions. The current burden of cancer is estimated at $200 billion per annum, and with our graying population, expected to increase to $1.5 trillion per annum.

REVIEWS

1. Lieb J. “Antidepressants, eicosanoids and the prevention and treatment of cancer.” Plefa (2001) 65(5&6) 233-239
2. Lieb, J. “Antidepressants, prostaglandins and the prevention and treatment of cancer.” Medical Hypotheses (2007) 69, 684-689

3. Lieb, J. “The multifaceted value of antidepressants in cancer therapeutics.” Eur J Cancer 44 (2008) 172-174

4. Lieb,J.” Defeating cancer with antidepressants.” ecancermedicalscience. DOI. 10. 3332/eCMS.2008.88

THE CANCER KILLING EFFECTS OF ANTIDEPRESSANTS

5. Serafeim A, Holder MJ, Grafton G et al. Selective serotonin reuptake inhibitors directly signal for apoptosis in biopsy-like Burkitt lymphoma cells. Blood 2003 Apr 15; 101(8): 3212-9. Epub Dec 19

6. Honda T, Favalaro FG Jr, Kjanosik T et al. Efficient synthesis of (-) and (+)-tricyclic compounds with enone functionalities in rings A and C. A novel class of orally active anti-inflammatory and chemopreventive agents. Org Biomol Chem. 2003 Dec 21; 1(24): 4384-91. Epub 2003 Oct 31.

7. Levkovitz Y, Gil-Ad I, Zeidich E et al. Differential induction of apoptosis by antidepressants in glioma and neuroblastoma cell lines: evidence for p-c-Jun, cytochrome C, and caspase–3 involvement. J Mol Neurosci , 2005;27(1):29-42

8. Hsu SS, Huang CJ, Chen JS et al. Effect of nortriptyline on intracellular Ca2+ handling and proliferation in human osteosarcoma cells. Basic Clin Pharmacol Toxicol. 2004 Sep; 95(3): 124-30

9. Arimochi H, Morita K. Characterization of cytotoxic actions of tricyclic antidepressants on human HT29 colon carcinoma cells. Eur J Pharmacol, 2006 Jul 10; 541(1-2): 17-23

10. Daley E, Wilkie D, Loesch A, Hargreaves IP. Kendall DA, Pilkington GJ, Bates TE. Chlorimipramine: a novel anticancer agent with a mitochondrial target. Biochem Biophys Res Commun 2005 Mar 11; 328(2): 623-32

11 Hisaoka K, Nishida A, Koda T, et al: Antidepressant drug treatments induce glial cell line-derivative neurotrophic factor (GDNF) synthesis and release in rat C6 glioblastoma cells. J Neurochem 2001 Oct; 79(1): 25-34

12. Spanova A, Kovaru H, Lisa V, Lukasova E, Rittich B. Estimation of apoptosis in C6 glioma cells treated with antidepressants. Physiol Res. 1997; 46(2): 161-4

13. Xia Z, Bergstrand A, DePierre JW, Nassberger L. The antidepressants imipramine, clomipramine and citalopram induce apoptosis in human acute myeloid leukemia HL-60 cells via caspase–3 activation. I Biochem Mol Toxicol. 1999; 13(6): 338-47

14. Hsu SS, Huang CJ, Chen JS, et al. Effect of nortriptyline on intracellular Ca2+ handling and proliferation in human osteosarcoma cells. Basic Clin Pharmacol Toxicol. 2004 Sep; 95(3): 124-30

15. Chou CT, He S, Jan CR. Paroxetine–induced apoptosis in human osteosarcoma cells: activation of p38 MAP kinase and caspase-3 pathways without involvement of (Ca2+) elevation. Toxicol Appl Pharmacol 2007 Feb 1: Feb 1; 218(2): 265-73

16. Pan CC, Cheng HH, and Huang CJ et al. The antidepressant mirtazapine induced cytosolic Ca2+ elevation and cytotoxicity in human osteosarcoma cells. Chin J Physiol. 2006 Dec 31; 49(6): 290-7

17. Toki S, Donati RJ, Rasenick MM. Treatment of C6 glioma cells and rats with antidepressant drugs increases the detergent extraction of G (s alpha) from plasma membrane. J Neurochem . 1999 Sep; 73(3): 1114-20

18. Snyder SW, Egorin MJ, Zuhowski EG, Schimpff EC, Callery PS. Effects of the monoamine oxidase inhibitor, tranylcypromine, on induction of HL60 differentiation by hexamethylene bisacetamide and N-acetyl-1.6-diaminohexane. Cancer Commun.1990; 2(7): 231-6

19. Tang KY, Lu T, Chang CH et al. Effects of fluoxetine on intracellular Ca2+ levels in bladder female transitional carcinoma (BFTC) cells. Pharmacol. Res. 2001 May; 43(5); 503-8

20. Elojeimy S, Holman DH, El-Zawahry A et al. New insights into the use of desipramine as an inhibitor for acid ceramidase. FEBS Lett. 2006 Aug 21; 580(19): 4751-6. Epub 2006 Aug 4.

21. Mal’tseva LF. Effect of serotonin antagonists and monoamine oxidase inhibitors on the antineoplastic effects of serotonin. Farmakol Toksikol. 1968 Nov-Dec; 31(6): 735-8

22. Albouz S, Tocque B, Hauw JJ et al. Tricyclic antidepressant desipramine induces stereospecific opiate binding and lipid modification in rat glioma C6 cells. Life Sci. 1982 Dec 6; 31(23): 2549-54.

23. Freire-Garabal M, Rey-Mendez M, Garcia-Vallejo LA et al. Effects of nefadazone on the development of experimentally induced tumors in stressed rodents. Psychopharmacology (Berl). 2004; 176(3-4); 233-8. Epub. 2004 May 26.

24. Freire-Garabal M, Nunez MJ, Pereiro D et al. Effects of fluoxetine on the development of lung metastases induced by operative stress in rats. Life Sci. 1998; 63(2): PL31-8

25. Basso A M, Depiante-Depaoli M, Molina VA. Chronic variable stress facilitates tumoral growth: reversal by imipramine administration. Life Sci 1992; 50(23): 1789-96

26. McCormick DL, Spicer AM, Hollister JL. Differential effects of tranylcypromine and imidazole on mammary carcinogenesis on rats fed low and high fat diets. Cancer Res 1989 Jun 15; 49(12): 3168-72.

27. Tsuruo T, Iida H, Nojiri M, Tsukagoshi S, Sakurai Y. Potentiation of chemotherapeutic effect of vincristine in vincristine resistant tumor bearing mice by calmodulin inhibitor clomipramine. J Pharmacobiodyn. 1983 Feb; 6(2): 145-7

28. Abdul M, Logothetis CJ, Hoosein NM. Growth-inhibitory effects of serotonin uptake inhibitors on human prostate carcinoma cell lines. J Urol. 1995 Jul; 154(1):247-50.

29. Tocque B, Albouz S, Boutry JM, Le Saux F, Hauw JJ, Bourdon R et al. Desipramine eliciits the expression of opiate receptors and sulfogalactosyleramide synthesis in rat C6 glioma cells. J Neurochem 1984 Apr; 42(4):1101-6.

INHIBITION OF CELL PROLIFERATION BY ANTIDEPRESSANTS

30. Nordenberg J, Fenig E, Landau M, Weizman R, Weizman A. Effects of psychotropic drugs on cell proliferation and differentiation. Biochem Pharmacol. 1999 Oct 15; 58(8): 1229-36.

31. Sauter C. Cytostatic activity of commonly used tricyclic antidepressants. Oncology 1989; 46(3): 155-7

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32. Volpe DA, Ellison CD, Parchment RE, Grieshaber CK, Faustino PJ. Effects of amitriptyline and fluoxetine upon the in vitro proliferation of tumor cell lines.J Exp Ther Oncol. 2003 Jul-Aug; 3 (4): 169-84

PROTECTION OF NONMALIGNANT HUMAN CELLS FROM IONIZING RADIATION AND CHEMOTHERAPY TOXICITY

33. Seymour CB, Mothersill C, Mooney R, Moriarty M, Tipton KF. Monoamine oxidase inhibitors l-deprenyl and clorgyline protect nonmalignant human cells from ionizing radiation and chemotherapy toxicity. Br J Cancer. 2003 Nov 17; 89(10): 1979-86

REVERSAL OF MULTIDRUG RESISTANCE BY ANTIDEPRESSANTS

34. Peer D, Margalit R. Fluoxetine and reversal of multidrug resistance. Cancer Lett. 2006 Jun 18; 237(2): 180-7

35. Varga A, Nugel H, Baehr R, et al. Reversal of multidrug resistance by amitriptyline in vitro. Anticancer Res. 1996 Jan-Feb; (1): 209-11

THE MITOCHONDRIA TARGETING PROPERTIES OF ANTIDEPRESSANT

36.Neuzil J, Wang XF, Dong LF, Low P, Ralph SJ. Molecular mechanism of “mitocan”- induced apoptosis in cancer cells epitomizes the multiple roles of reactive oxygen species and Bcl family proteins. FEBS Lett. 2006 Oct 2; 580(22)5125-9.Epub 2006 Jun 12.

37.Pilkington GJ, Parker K, Murray SA. Approaches to mitochondrially mediated cancer therapy. Semin Cancer Biol. 2008 Jun; 18(3):226-35. Epub 2007 Dec 8.

38.Langbein S, Frederiks WM, zur Hausen A, Popa J, Lehmann J, Weiss C, Alken P, Cov JF. Metastasis is promoted by a bionergetic switch: new targets for progressive renal cell cancer. Int J Cancer 2008 Jun 1; 122(11):2422-8.

39..Goovadze V, Orrenius S, Zhivotovsky B. Mitochondria in cancer cells: what is so special about them? Trends Cell Biol. 2008 Apr; 18(4):165-73. Epub 2008 Mar

40. Ristow M. Oxidative metabolism in cancer growth. Curr Opin Clin Nutr Metab Care. 2006 Jul; 9(4):339-45.

41.Arimochi H, Morita K.”Desipramine induces apoptotic cell death through nonmitochondrial and mitochondrial pathways in different types of human colon carcinoma cells.”Pharmacology. 2008; 81(2):164-72. Epub 2007 Nov 19.

42.Moreno- Fernandez AM, Cordero MD, de Miguel M, Delgado-Rufino MD, Sanchez-Alacazar JA, Navas P. Cytotoxic effects of amitriptyline Y, Zaragoza C, Johnson MS, Darley-Usmar VM. Induction of the permeability transition and cytochrome c release by line in human fibroblasts. Toxicology. 2008 Jan 14; 243(1-2):51-8. Epub Sep 26.

43. Nahon E, Israelson A, Abu-Hamad S, Varda SB. Fluoxetine (Prozac) interaction with the mitochondrial voltage-dependent anion channel and protection against apoptopic cell death. FEBS Lett. 2005 Sep 12; 579(22):5105-10

44.Daley E, Wilkie D, Loesch A, Hargreaves IP, Kendall DA, Pilkington GJ, Bates TE. Chlomipramine, a novel anticancer agent with a mitochondrial target. Biochem Biophys Res Commun. 2005 Mar 11; 328(2)623-632

45.Lender A, Shiva S, Levenson AL, Oh J 15-deoxy-Delta12-prostaglandin J2 in mitochondria. Biochem J 2006 Feb 15; 394(Pt1):185-95

46.Fang KM, Shu WH, Chang HC, Mak OI. Study of prostaglandin receptors in mitochondria of human lung carcinoma cell line A549. Biochem Soc Trans 2004 Dec; 32(Pt6):1078-80

47 Altinoz MA, Gedikoglu G, Sav A, Ozcan E, Ozdilli K, Bilir A, Del Maestro RF. Medroprogesterone acetate induces c6 glioma chemosensitization via antidepressant-like lysosomal phospholipidosis/myelinosis in vitro. Int J Neurosci. 2007 Oct; 117(10):1465-80.

48. Joseph B, Marchetti P, Formstecher P, Kroemer G, Lewensohn R, Zhivtotsky B. Mitochondrial dysfunction is an essential step for killing of non-small cell lung carcinomas resistant to conventional treatment. Oncogene. 2002 Jan 3; 21(1):65-77.

MISCELLANY

49. Penninx BW, Guralnik JM Pahor M et al. Chronically depressed mood and cancer risk in older persons. J Natl Cancer Inst. 1998 Dec; 90(24): 1888-93

50. Ronson A. Neurotrophic theories of stress and neurobiology of antidepressants: applications in psycho-oncology. Bull Cancer. 2007 May 1; 94(5): 431-8

51. Steingart AB, Cotterchio M. Do antidepressants cause, promote or inhibit cancers? J Clin Epdemiol 1995 Nov; 48(11): 1407-12

52. Ballin A, Gershon V, Brener J, Weizman A, Meytes D. The antidepressant fluvoxamine increases natural killer cell counts in cancer patients. Isr J Med Sci 1997 Nov; 33(11): 720-3

STIMULATING 15-HYDROXYPROSTAGLANDIN DEHYDROGENASE WITH ANTIDEPRESSANTS

53. Myung SJ, Rerko RM, Yan M et al. 15-hydroxyprostaglandin dehydrogenase as an in vivo suppressor of colon tumorigenesis. Proc Natl Acad Sci U.S.A 2006 Aug 8; 103 (32): 12098-102. Epub 2006 31

54. Yan M, Rerko RM, Platzer P et al. 15-hydroxyprostaglandin dehydrogenase, a Cox-2 oncogene antagonist, is a TGF-beta-induced suppressor of human gastrointestinal cancers. Proc Natl Acad Sci U.S.A 2004 Dec 14; 101(50): 17468-73. Epub 2004 Dec 1.

55. Mak O and Chen S. Effects of two antidepressant drugs imipramine and amitriptyline on the enzyme activity 15-hydroxyptostaglandin dehydrogenase purified from brain, lung, liver and kidney of mouse. Prog Lipid Res 1986; 25:153-5

CLINICAL

56. Jozuka H, Jozuka E, Suzukei M, Takeuchi S, Takatsu Y. Psycho-neuro-immunological treatment of hepatocellular carcinoma with major depression-a single case report. Curr Med Res Opin 2003; 19(1): 59-63

OF HISTORICAL INTEREST

These articles could not be retrieved, but their citations show that the idea of treating cancer with monoamine oxidase inhibitors or tricyclic antidepressants has been around for a long time.

57. Uzer Y, Shnider BI, Gold GL. A double-blind study with iproniazid in patients with far-advanced cancer. Antibiotic Med Clin Ther 1960 Dec; 7:777-81

58. Branco F. Iproniazid (Marsilid) in cancerology. Arq Patol 1959 Nov; 31:451-66.

59. Tettoni E, Sinistrero, G. Concerning the effects of a new imino-stilbene derivative (Insidon) in cancer in the course of radiotherapy treatment. Minerva Med 1963 Dec 19; 54:3898-900

Julian Lieb, M.D was a Yale medical school psychiatrist, before switching to the immunopharmacology of infectious disorders and cancer. He is an authority on the role of prostaglandins in depression, infectious disorders, and cancer. Dr Lieb has authored or coauthored forty five articles and nine books.

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