title: Autism's cancer connection: the anti-proliferation hypothesis and why it may matter.
abstract: Autism remains an idiopathic disorder in 90% of cases. Recent prevalence, heritability, and genetic studies are suggestive that epigenetic and, therefore, environmental factors are important in autism pathogenesis. Among the environmental factors, only some uncommon viral infections and certain drugs have been conclusively linked to autism causation. Thalidomide, valproate, terbutaline and, most recently, antidepressants are the main drugs reported to elevate autism risk. This article discusses a phenomenal relationship between the drugs reported to elevate autism risk and the antiproliferative effects of the same drugs and/or analogs of the drugs in cancer cells. Cancer treatment has entered a new era-epigenetic therapy. In cancer cell lines, thalidomide is antiangiogenic and antiproliferative via suppression of tumor necrosis factor-alpha (TNF-α) and downstream effects on the nuclear factor (NFκB) cascade. Valproate shares similar mechanisms with thalidomide, but is best known in cancer therapy for its epigenetic effects as a histone deacetylase inhibitor. Terbutaline, a beta-adrenergic agonist, acts via adenylyl cyclase and cAMP-PKA signal transduction. Current cancer therapy aims to exploit this epigenetic pathway by developing site-selective cAMP analogs. Last, it has long been noted in preclinical studies that some antidepressants are antiproliferative in cancer cells but the mechanisms remain unclear. Based on a systematic review of these drugs, it is hypothesized that all central nervous system-acting drugs, which show antiproliferative effects in cancer cell lines, share the potential to elevate autism risk when administered prenatally. It is further posited that, in autism, the drugs act as "triggers" that disturb the pro-proliferative fetal milieu using the same, mainly epigenetic, mechanisms that they demonstrate in rapidly proliferating cancer cells. In addition to their direct antiproliferative effects, evidence is suggestive that the drugs may lock in the pro-inflammatory bias of the prenatal immune system by preventing normal perinatal dendritic cell maturation. This unifying hypothesis for how structurally different drugs elevate autism risk could help focus research on other drugs, or other xenobiotics, that may elevate autism risk. For example, there is evidence that an old class of drugs, the phenothiazines, is antiproliferative in cancer cell lines via inhibition of calmodulin and/or histaminic pathways. Promethazine, one of the first heterocyclic phenothiazines synthesized, is commonly prescribed during pregnancy; however, its role in elevating the risk of autism has not been investigated. Based on the anti-proliferation hypothesis, more studies of promethazine and other similar drugs are suggested to evaluate their potential to elevate autism risk following prenatal exposures.
authors.affiliation: Fincastle Family Medicine, LaFollette, TN, United States. Electronic address: docward@comcast.net.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Ward
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology*; D001321:Autistic Disorder / Q000139:chemically induced*; D063185:Epigenetic Repression / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D013726:Terbutaline; D013792:Thalidomide; D014635:Valproic Acid
chemical_list: D000970:Antineoplastic Agents; D013792:Thalidomide; D014635:Valproic Acid; D013726:Terbutaline