Antidepressants, prostaglandins and the prevention and treatment of cancer

Medical Hypotheses (2007) 69, 684–689

http://intl.elsevierhealth.com/journals/mehy

Antidepressants, prostaglandins and the prevention and treatment of cancer Julian Lieb

*

22 Rimmon Road, Woodbridge, CT 06525, United States Received 17 January 2007; accepted 18 January 2007

Summary Among the putative mechanisms of carcinogenesis are up-regulation of cyclooxygenase, the synthesis and expression of oncogenes, viral activation, signal disruption, failed apoptosis, tumor initiation and promotion, angiogenesis, metastasis, immunosuppression, telomerase activity and autoimmunity. All are regulated by prostaglandins. Observable and radiographic regression of cancer has been documented in patients taking non-steroidal, antiprostaglandin drugs such as indomethacin and ibuprofen. Antidepressants, too, have prostaglandin-inhibiting properties, and in vivo and in vitro evidence of their antineoplastic actions is emerging. c 2007 Published by Elsevier Ltd.



Introduction Many lines of evidence point to antidepressants as potent antineoplastic agents. They include in vitro and in vivo studies, a population study, copious studies on prostaglandins as immunosuppressants and carcinogenics, and neglected studies on antidepressants as prostaglandin inhibitors. Synthesized by every cell in the body, prostaglandins are ubiquitous in cellular function and dysfunction, a vast body of evidence illuminating their role in cancer [1–6]. Isolation of isoforms of the prostaglandin-synthesizing enzyme cyclooxygenase has stimulated interest in the potential role of selective cyclooxygenase-2 inhibitors in cancer treatment and prevention [7]. The anti-prostaglandin properties of antidepressants and their potential * Tel.: +1 2033971226. E-mail address: [email protected]



0306-9877/$ - see front matter c 2007 Published by Elsevier Ltd. doi:10.1016/j.mehy.2007.01.036

role in cancer prevention and treatment have been neglected. Five years ago I proposed that antidepressants might have cancer preventing and treating properties [8]. Subsequently, many in vitro and in vivo studies have appeared confirming that idea. In this article, I will condense the prior article and supplement it with confirmatory studies.

Prostaglandins in carcinogenesis Prostaglandins are incriminated in such putative mechanisms of carcinogenesis as up-regulation of cyclooxygenase [9,10], oncogene synthesis and expression [11,12], viral activation [13], signal disruption [14], failed apoptosis [15,16], tumor initiation and promotion [17], angiogenesis [18,19], metastasis [20], immunosuppression [21], autoimmunity [22] and telomerase activation [23]. Prostaglandins regulate the synthesis, inhibition and expression of genes and oncogenes [24,25] and

Antidepressants, prostaglandins and the prevention and treatment of cancer the replication of cells [26]. The isolation of cyclooxygenase-2 [27] and the synthesis of selective cyclooxygenase-2 inhibitors stimulated research into the expression of this isoform in apoptosis and cancer, cyclooxygenase-2 overexpression inhibiting apoptosis [7]. Chronic use of such PG inhibitors as aspirin and ibuprofen reduces the risk of colon and other cancers [28,29]. Induction of prostaglandins suppresses the antimicrobial activity of the immune system, with pathogens responsible for 20% of all cancers [30]. Immunosuppression is a cause and effect of cancer, increase in prostaglandins at the primary tumor site blocking surveillance by the immune system [21]. In a paradoxical counterpoint to immunosuppression, numerous autoimmune phenomena are also apt to occur in patients with cancer [31,32]. Malignant tumors are diagnosed with increased frequency in patients with such autoimmune disorders as pemphigus, myasthenia gravis, and the Eaton– Lambert syndrome [33]. The paraneoplastic syndrome includes a variety of prostaglandin-related neurological, hematological, metabolic, cardiovascular and dermatological disorders [34]. Prostaglandins are largely responsible for cancer cachexia and wasting [35].

Antidepressants as inhibitors of prostaglandins Horton was the first to show that prostaglandins have powerful actions on the brain, stimulating intensive study of the actions of psychotropic drugs on prostaglandins [36]. Subsequently Lee showed that by inhibiting the mobilization of arachidonic acid, antidepressants inhibit prostaglandin E2, phenelzine (Nardil) exerting a more powerful antiprostaglandin effect than indomethacin [37]. The antidepressant tranylcypromine lowers concentrations of the depressant prostaglandin D2 in the brains of animals [38]. Horrobin showed that tricyclic antidepressants are weak agonists and powerful antagonists of both prostaglandin E2 and thromboxane B2 [39,40]. Attempts to stimulate the prostaglandin-degrading enzyme, 15-hydroxyprostaglandin dehydrogenase failed until 1986, when Mak and Chen showed that imipramine and amitriptyline do so [41].

Depression: a precursor of cancer In the Ward Jones lecture given at Manchester University in 1957, Sir Heneage Ogilvie commented, ‘‘I have slowly come to frame in my mind an apho-

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rism that can never be stated as such, because no statistics can be advanced to support it: ‘The happy man never gets cancer. . .The instances where the first recognizable onset of cancer has followed almost immediately on some disaster, bereavement, the breakup of a relationship, a financial crisis, or an accident are so numerous that they suggest that some controlling force that has hitherto kept the outbreak. . . in check has been removed’’ [42]. In 1998 Penninx and her coworkers at the National Institute of Aging confirmed Ogilvie’s hypothesis: chronically depressed people over the age of seventy are 88% more likely to develop cancer and twice as likely to die of it than their cheerful peers [43].

The immunostimulating and antimicrobial properties of antidepressants Antidepressants augment natural killer cell activity in vitro and in vivo [44], the monoamine oxidase inhibitor tranylcypromine (Parnate) enhancing cell-mediated immunity [45], Monoamine oxidase inhibitors can reverse tuberculosis, cold sores, genital herpes, upper respiratory infections and plantar warts [46,47]. Tricyclic antidepressants can reverse canker sores [48], alleviate the pain of shingles and post herpetic neuralgia [49], destroy in vitro leishmania major and minor [50], inhibit the growth of Giardia lamblia [51], destroy Trypanasoma parasites [52], inhibit the growth of malaria parasites [53] and restore sensitivity to chloroquine of resistant organisms [54]. Various specific serotonin reuptake inhibitors can destroy such fungi in vitro as Candida and Aspergillus [55], remit recurrent vulvovaginal candidiasis in vivo [56], and have antibacterial properties alone [57] or synergistically with various antibiotics [58].

Antineoplastic properties of antidepressants in vitro Nefadazone reduces stress-induced tumors in rodents [59], and fluoxetine stress-induced lung metastases in rats [60]. Such antidepressants as imipramine, desipramine, amitriptyline and fluoxetine are lethal to human colon carcinoma cells [61,62]. Selective serotonin reuptake inhibitors such as fluoxetine signal for programmed cell death in Burkitt lymphoma cells [63]. Nortriptyline [64] and desipramine [65] destroy human osteosarcoma cells, and various specific serotonin reuptake inhibitors and the tricyclic clomipramine glioma

686 and neuroblastoma cells [66,67]. Novel tricyclic drugs inhibit the proliferation of breast cancer cells [68]. 15-Hydroxyprostaglandin dehydrogenase is the primary prostaglandin-degrading enzyme, highly expressed in normal colon mucosa but lost in human colon cancers. Lack of this enzyme promotes the earliest steps of growth of benign as well as malignant colon tumors [69], and tricyclic antidepressants are known to stimulate it [41].

Antineoplastic properties of antidepressants in vivo A woman suffering from major depression and advanced liver cancer (hepatoma) was treated with psychotherapy, the antidepressant fluvoxamine (Luvox), glycyrrhizin acid and dehydroepiandrosterone (DHEA). Various indices of defective immune function normalized, and her liver function tests improved. At follow-up two-and-a-half-years later she was well and symptom free [70]. In 1990 a 60-year-old woman had a mastectomy for inflammatory breast cancer, followed by excision of infiltration of the chest wall. She was given a prognosis of less than a year. I treated her with various antidepressants, and when she relocated in 2003 was in apparent good health. Antidepressants reduce the severity and frequency of hot flashes in patients treated with chemotherapy for breast cancer [71], Velafaxine (Effexor) can reverse the acute neurosensory symptoms secondary to oxaliplatin chemotherapy [72]. The monoamine oxidase inhibitors deprenyl and clorgyline protect nonmalignant human cells from ionizing radiation and chemotherapy toxicity [73], and such antidepressants as nefadazone are capable of reversing chemotherapy-induced vomiting [74].

Conclusions Enzymes in the arachidonic acid pathways are sites of action of antidepressants [37]. By maintaining these enzymes within physiological limits [41], antidepressants may prevent or reverse cancer. The ability of antidepressants to alleviate or reverse such autoimmune disorders as migraine, rheumatoid arthritis, asthma and multiple sclerosis strengthens the case for their potential value in cancer [75]. Antidepressants are of value in managing cancer pain, as they have analgesic properties and potentiate opiates [76]. The antimicrobial and immunopotentiating properties of antidepressants may mitigate the immunosuppressive actions of chemotherapy; it is possible that antidepres-

Lieb sants could also enhance the response to chemotherapy and radiation, and mitigate the tachyphylaxis that may undermine such therapies. Excessive synthesis of prostaglandin E2 in brain cells depresses mood, and may induce various disorders of defective immunity, autoimmunity and neoplasia. As prostaglandins regulate the synthesis, inhibition and expression of genes, the precondition may be excessive brain synthesis of prostaglandin E2, the variations determined by genes or by nuances in the enzymes engaged in prostaglandin synthesis, metabolism and degradation. As depression may lower the threshold for stress and reduce compliance with chemotherapy, antidepressants should be of value in enhancing compliance [77]. It would be surprising if the antiviral and immunostimulating properties of antidepressants did not lend themselves to cancer prevention and treatment [78]. These properties challenge such paradigms as stem cells, genomics and stem cells. In ‘‘Against Method’’ Paul Feyerabend noted that suppressing a paradigm in preference to one politically favored could permanently damage society [79]. None of the in vitro studies mentions prostaglandins, yet all show that antidepressants readily destroy cancer cells. Arriving at the same conclusion while using different premises supports the conclusion. As the response to antidepressants is specific, patients may require multiple trials before responding, or may develop immunity and relapse [80]. The omnipresence of paradox warns that antidepressants must be capable of initiating or accelerating cancer. Epidemiological studies do not support a relationship, but clinical reports continue to appear, including that of three cases in men with malignant and premalignant disease of the breast taking specific serotonin reuptake inhibitors for depression [81]. Maintaining an index of suspicion, close clinical observation, and limiting the duration of non-or-negative response drug trials can mitigate paradox. Paradoxes are apt to occur in the context of non-response or tachyphylaxis. More than two decades have elapsed since lithium and antidepressants were shown to have immunostimulating and antimicrobial properties, and their antineoplastic actions could well suffer the same fate at the hands of Big Pharma and other special interests. The innovations fulfill the criteria David Horrobin defined as ethical: big effects, large populations, safety and minimal cost [82]. Ethics dictate that those touched by cancer and their physicians should be informed of the resisted paradigm shift. There is much room for an additional resource for palliation, and the prospect of arrest or even reversal of

Antidepressants, prostaglandins and the prevention and treatment of cancer cancer. This is an opportunity for clinical case reporting, as controlled studies do not lend themselves to situations in which patients may respond selectively to only one or two out of twenty antidepressants. Placebo control is not placebo control when both drugs are inert. Medical innovations are held to be formulated in the laboratories of medical schools and pharmaceutical companies, and make their way to the bedside. In truth, the traffic is often in the opposite direction. Physicians should not wait for policy makers to sanction the use of antidepressants for cancer. The anti-prostaglandin, immunostimulating, antimicrobial and antineoplastic paradigm of antidepressants is unlikely to be improved on, placing in bold relief the failure of Big Pharma to develop effective, safe and inexpensive antineoplastic agents. Lithium has anti-prostaglandin, immunostimulating and antimicrobial properties, but evidence for an antineoplastic action is presently much weaker than that of antidepressants.

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