Chlorpromazine reduces UV-induced squamous cell carcinogenesis in hairless mice and enhances UV-induced DNA damage in cultured cells

Abstract

Summary Administration of the photoactivable compound chlorpromazine (CPZ) to SKH-1 hairless mice via their drinking water (CPZ, 0.01%) significantly reduced the rates of accumulation and yields of squamous cell carcinomas induced by long-term repeated exposures of these animals to solar UV radiation. This protective effect of CPZ was partially reversed in mice given a single injection of ethyl nitrosourea at birth. In in vitro studies, the presence of CPZ (0.2 mM) in mammalian cell cultures enhanced the yield of DNA singlestrand breaks induced in the cells by exposure to monochromatic UVA radiation at 334 nm. Collectively, the results suggest that CPZ may exert antineoplastic effects against UV-induced skin tumours by the induction of DNA damage.Chlorpromazine CPZ, 2-chloro-N,N-dimethyl-10-phenothiazine-10-propanamine), a commonly prescribed sedative, tranquiliser and anti-emetic, is also a highly photoactive compound (Kochevar, 1987). Photoactivation of CPZ produces oxidising CPZ radicals (including promazyl, peroxy and hydroxyl radicals) that are known to have cytotoxic effects on biological systems (Ciulla et al., 1986;Decuyper et al., 1986;Fujita et al., 1981). Therefore, the exposure of individuals ingesting CPZ to high fluences of ultraviolet A (UVA) radiation (radiation between 320nm and visible light, such as that found in solar UV or tanning booth radiation) should increase the body burden of oxidising radicals, especially in the epidermal tissues, into which the longer wavelengths of UVA readily penetrate (Bruls et al., 1984). This increment in tissue free radicals should enhance tumorigenesis, in keeping with the postulated role of free radicals as promoters of neoplasia (Gilbert, 1972;Greenstock & Ruddock, 1978;Greenstock & Wiebe, 1978;Pryor, 1978; Troll, 1978;Ames, 1983;Kinsella et al., 1983;Marx, 1983;Cerutti, 1985;Jones, 1985). Therefore, it might be anticipated that the ingestion of phenothiazines that are susceptible to photoactivation would enhance tumorigenic risk. Contrary to such expectations, however, clinical observations (in cancer patients given CPZ as a nausea suppressant during chemotherapy), epidemiological studies of mental hospital inmates receiving phenothiazine therapy and experimental evidence from studies with rodents indicate that phenothiazines such as CPZ may have antineoplastic activity (Jones, 1985;Darkin et al., 1984).Because none of the foregoing studies of phenothiazine antineoplasia addressed the issue of phenazine photoactivation and the biological effects of the resultant oxidising free radicals, we were prompted to perform an experiment to test possible enhanced or diminished neoplastic effects of dietary CPZ in groups of rodents exposed to carcinogenic solar UV radiations. The preliminary data have been reported previously (Peak et al., 1987b

Photosensitization of Biomolecules by Phenothiazine Derivatives

“…On the contrary, derivatives containing a hydrogen or a trifluoromethyl group instead of chlorine in position 2 of the phenothiazinic ring, were not photogenotoxic. Two photocarcinogenicity in vivo studies with CPZ have yielded contradictory results: Peak et al [148] observed a strong reduction of UV induced skin tumor formation while Kelly et al [140] found a strong enhancement of UV induced skin carcinogenesis. Both laboratories used hairless SKH mice and employed lamps with broad emission spectra including visible light.…”

“…DNA breakage alkaline elution [140] and Comet assay [141] give further evidence of the genotoxicity actions of the compounds. As far as detailed in the reports the compounds and the cells were irradiated concomitantly.…”

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“…1975;SHENOY and GOPALAKRISHNA 1978;GEORGE et al 1980;GEORGE and SINGH 1984). PEAK et al (1989) reported that CPZ treatment increased the frequency of DNA strand breaks induced by UV radiation in cultured mammalian cells. Similarly, CPZ has also been found to enhance the damage caused by alkylating agents and caffeine (COHEN 1973(COHEN , 1975LIALIARIS et al 1988).…”

The phenomenon of phototoxicity and long-term risks of commonly prescribed and structurally diverse drugs

“…There are no reports of an increased risk of skin cancer due to the phototoxicity of CPZ [ 38 ]. Instead, it may suppress UV-carcinogenesis [ 167 , 168 ]. It is hypothesized that CPZ may act as an antioxidant and neutralize the potential harmful effects of the radicals on the DNA, thus limiting genotoxicity [ 167 , 168 ].…”

“…Instead, it may suppress UV-carcinogenesis [ 167 , 168 ]. It is hypothesized that CPZ may act as an antioxidant and neutralize the potential harmful effects of the radicals on the DNA, thus limiting genotoxicity [ 167 , 168 ]. Another possible mechanism is that CPZ may increase the activity of DNA repair or increase immune surveillance against UV-induced skin cancers [ 168 ].…”