Among the mechanisms of carcinogenesis are oncogene synthesis and expression, upregulation of cyclooxygenase, accelerated cell replication, failed apoptosis, viral activation, disruption of signaling pathways, autoimmunity, immunosuppression, angiogenesis and metastasis. All fall within the orbit of eicosanoids and the enzymes that synthesize them. Antidepressants may be of benefit in the prevention and treatment of cancer, as they inhibit the synthesis, antagonize the actions and accelerate the degradation of such eicosanoids as prostaglandins and thromboxanes.
Synthesized primarily by every cell membrane in the body, eicosanoids are ubiquitous in physiology and disease. Theessential fatty acid arachidonic acid (AA) is the primaryprecursor of such eicosanoids as prostaglandins(PGs), leukotrienes (LTs), thromboxanes (TXs) and lipoxins.
Since the identification of eicosanoids in1968 as potentially carcinogenic, an immense body of research has accumulated illuminating their ubiquitous role incancer. Isolation of isoforms of the PG-synthesizing enzymecyclooxygenase (COX) has stimulated interest in the potentialrole of selective COX-2 inhibitors in cancer treatment andprevention. The antiprostaglandin properties of antidepressants and their implications in cancer prevention and treatment have been neglected.
In 1968 Williams and coworkers reported high levels of PGs in the thyroid and plasma of patients with medullary cancer of thethyroid. In 1976 Goodwin and coworkers reported increased synthesis of prostaglandin E2 (PGE2) in suppressor T-cells ofpatients with Hodgkin’s disease. Numerous studies subsequently revealed elevated levels of PGsin solid tumors and in the immune cells and body fluids ofcancer patients.[3–12] Thousands of studies in animals and humans confirm the participation of eicosa- noids incarcinogenesis.[13–20]
PGs are involved in regulating the synthesis and expres- sion ofgenes and oncogenes. Genes and oncogenes in turn regulate suchPG-synthesizing enzymes as cyclo- oxygenase-2 (COX-2) andthe expression of PGs.[21–31]
The isolation of such isoforms of cyclooxygenase as COX-2 and the synthesis of selective COX-2 inhibitors havestimulated research into the expression of this isoform in cancer and its role in apoptosis. COX-2 overexpression converts procarcinogenstocarcinogens and inhibits apoptosis.
COX-2 is upregulated in such cancers as those of the head and neck, breast, lung, pancreas, bladder, cervix, prostate andmesothelium.32–45SuchPG-synthesis inhibitors as indomethacin andsulindac can induce regression of colon polyps in vivo andex vivo. In population studies, chronic use of such PG-synthesis inhibitors as aspirin and ibuprofen has reduced the risk of colon cancer by as much as 50%.
In 1983 Armato and Andreis reported that prostaglandinF1a and F2a intensely stimulate primary neonatal rat hepatocytes, F2a more powerfully stimulating DNA synth- esisthan arachidonic acid.
In 1990 Goodlad and coworkersreported that the increase in gastric mucosal mass induced by misoprostol in the stomach of dogs is due to increased cell production. The increase in mucosal mass was the result of adramatic increase in the foveolar surface mucous cells. Other studies have shown a para-doxical inhibitory effect of PGs on DNA synthesis.[50,51]
PGs and their synthesizing enzymes block apoptotic signals.Such nonsteroidal anti-inflammatory compounds as sulindac andpiroxicam can induce apoptosis in normal and cancer cells.[52–57]
Induction of PGs is essential if viruses, including the oncogenic, are to complete their replicative cycles.Indirectly, induction of PGs suppresses the antiviral activity of the immune system.[58,59]
Eicosanoids and their synthesizing enzymes are key factors in many signaling events. Disruptions of signaling pathways are incriminated in many cancers.[60–63]
In a paradoxical counterpoint to immunosuppression, numerous autoimmune phenomena are reported in patients with cancer. Malignant tumors are diagnosed with increased frequency in patients with such auto-immune disorders as pemphigus, myasthenia gravis and the Eaton–Lambert syndrome. Apoptosis and PGs appear to play dual roles in autoimmunity and in cancer.[64–66]
Immunosuppression is both a cause and effect of cancer, avicious cycle.[67–70] Imai and his colleagues did an 11-year follow-up study to assess the level of naturalcytotoxic activity of such lymphocytes as natural killer (NK) cells and the incidence of cancer and death. Their results showed that medium and high cytotoxic activity is associatedwith reduced cancer risk, and low activity is associated with increased cancer risk.
Increase in PGs at the primary tumor focus may block surveillance by the immune system. PGs are potent suppressants of lymphocytes, and an increase in plasma PGs may contribute to a suppressive environment for lymphocyte function.
G.I. Deichman has shown that tumor progression in vivo isassociated with the appearance and selection of tumor cellswith a high level of antioxidant catabolizing activity and for the immediate release of prostaglandin E2 on contact with naturalkillers, macrophages and neu- trophils.
The expression of these phenotypes provides tumor cells with two mechanisms of local protection against effectors of innate and acquired antitumor activity. In primary viral carcinogenesis the selection of cells expressing these phenotypes begins within the latent period and can be completed by appearance of primary tumors.
In 1983, Karmali and her coworkers reported that increased TX formation in human breast cancer specimensis associated with three clinical variables – tumor size, axillary lymph node metastases and distant metastases.The mechanisms in which PGs and TXs induce metastasis include induction of proteolyticenzyme production, neovascularization and subversion of the immune response.
The initiation of metastasis is thought to involve the adherence of circulating tumor cells to endothelial cells or to basement membranes. PGs and TXs play a role in adherence, with local TX concentrations possibly determining the sites of metastasis.[73–88]
The paraneoplastic syndrome includes a variety of neurological, hematological, metabolic cardiovascular and dermatological disorders. PGs are incriminated in many.[89–90]
Evidence from a variety of sources incriminates PGs in the pathogenesis of depression. Two-series PGs are elevated in the plasma, spinal fluid, and saliva of depressives, and tranylcypromine directly lowers concentrations of the depressant prostaglandin D2 inthe brains of animals. Infusion of prostacyclin, a two-series PG into patients withRaynaud’s disease as a vasodilator characteristically induces acutedepression.
Horton’s 1966 report that PGs have powerful actions on thebrains of chicks and cats  stimulated intensive study of theactions of psychotropic drugs on PGs. Horrobin, Murphy and Wang and their coworkers showed that lithium carbonate inhibits prostaglandin E1 (PGE1).[97,98,99]
Recently, Chang showed that lithium decreases the turnover of arachidonate in various brain phospholipids.
Lee showed that by inhibiting the mobilization of AA acid, antidepressants inhibit PGE2, with phenelzine (Nardil) exertinga more powerful antiprostaglandin effect than indomethacin. Hong showed that tranylcypromine reduces the mobilization of archidonate, while Horrobin and his coworkersshowed that such tricyclic antidepressants as imipramineand chlomipramine are weak PG agonists and powerful antagonists.
Mtabaji and coworkers showed that tricyclicanti-depressants antagonize TXs. Attempts to activate the primary prostaglandin degrading enzyme, 15-hydroxy- prostaglandindehydrogenase, failed until 1986, when Oi Mak and T.Chen showed that imipramine and amitriptyline have powerful activatory effects on this enzyme.
Monoamine oxidase inhibitors, originally used in the treatmentof tuberculosis, have potent antiviral and immunoregulating properties. Thus it is not surprising that one of them is effective in treating a neoplastic disease.
The disease is stage III and IV Hodgkin’s disease, the monoamine oxidase Matulane (procarbazine) part of the MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) regimen.
In ignoring the actions ofmonoamine oxidase inhibitors on PGs, the manufacturer states, ‘There is evidence that the drug may act by inhibition of protein, RNA and DNA synthesis.’
In the Ward Jones lecture given at Manchester University in1957, Sir Heneage Ogilvie commented,
‘I have slowly come to frame in my mind an aphorism 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 outbreakyincheck has been removed.
In 1998 B. W. J. H. Penninx and her coworkers at the National Institute of Aging provided compelling support for Ogilvie’s hypothesis: chronically depressed people over theage of 70 are 88% more likely to develop cancer and twice as likely to die of it than their cheerful peers.
The Role of Antidepressants In Preventing Cancer
In interstices between cell membrane phospholipids and genes,membrane phospholipids and organelles, genes and enzymes, genes and proteins, PGs induce cancer. The places where PG-synthesizing enzymes convert AA acidor phospholipids to PGs are possible sites of action ofantidepressants.
By maintaining these enzymes within physiological limits, antidepressants may prevent cancer by preserving apoptosis and immune surveillance, inactivating viruses, activating suppressor genes, inhibiting oncogenesand normalizing cell replication.
The ability of antidepressantsto alleviate or remit such autoimmune disorders as migraine, rheumatoid arthritis, asthma and multiple sclerosis strengthens the case for their potentialvalue in cancer.
Depression incancer patients may be more an antecedent than a consequence of the disease.[121–124]
As depression lowers the threshold for stress and reduces compliance with adjuvant chemotherapy, antidepres- sants may be of value inenhancing compliance. It would be surprising if the antiviral and immunostimulating properties alone of antidepressants did not lend themselves to cancer prevention and treatment.[112–120]
Other than the finding that lithium inhibits various phospholipases, the actions of psychotropic agents on the arachidonic cascade has stimulated little recent research. The actions of antidepressants on such aspects of carcinogenesis as apoptosis, gene activation and suppression and the expression of COX and other enzymes appear to be fertile areas for basic and applied pharmacology.
The antiprostaglandin, antiviral and immunopotentiating properties of lithium carbonate suggest that it too is worthy of investigation in the prevention and treatment of cancer beyond that of its protective effects onhematopoeisis during chemotherapy.[126–134]
Drawbacks and Practical Considerations
As the response to antidepressants is highly specific, many patients require multiple trials before their depression responds. Some subjects are refractory to all antidepressants and many relapse due to tachyphylaxis.
PGs are capable of paradoxical pro-carcinogenic and anti-carcinogenic actions.[136-137].
Maintaining an index of suspicion, close clinical observation and limiting the duration of drug trials can mitigate such paradox.
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