Involvement of Multiple Signaling Pathways in Diallyl Sulfide Mediated Apoptosis in Mouse Skin Tumors

Many chemopreventive agents appear to target signaling intermediates in apoptosis-inducing pathways. Inherently,the process of neoplastic conversion selects against apoptosis to initiate, promote, and perpetuate the malignantphenotype. Thus, targeting apoptosis pathways in pre-malignant cells, in which these pathways are still relativelyintact, may be an effective module of cancer prevention. Diallyl sulfide (DAS), a naturally occurring organosulfide,present in garlic, is reported to have pleiotropic biological effects. DAS is known to inhibit chemically inducedtumors in a number of in vivo and in vitro studies. The aberration of tumor suppressor gene, p53 and the rasoncogene have been linked to the induction of multiple signaling pathways and to the resistance offered by cancercells to the apoptosis. Therefore, the present study was carried out to investigate the role of DAS on modulation ofmultiple p53 and ras-induced signaling pathways in 7,12-dimethylbenathacene (DMBA) induced skin carcinogenesis.The results showed that DAS up regulates expression of tumor suppressor protein p53 (wt p53) and its downstreamtarget molecule p21/waf1. Proapoptotic protein, bax was upregulated by DAS supplementation. An opposite trendwas observed in DMBA induced antiapoptotic proteins expressions, survivin and bcl-2, which were significantlydownregulated by DAS supplementation. In the present study we also demonstrated that DAS supplementationsignificantly reduces the expression of ras oncoprotein and to modulate expression of its signaling molecules includingPI3K/Akt and MAPKs. Western blot analysis demonstrated that DAS significantly reduced the DMBA inducedprotein expressions of PI3K/Akt and p38MAPK. However, DAS supplementation did not alter the expression JNK1and ERK1/2. Thus, our results confirm that DAS can adopt a multi-prong strategy to target multiple signalingpathways leading to induction of apoptosis and inhibition of growth of DMBA induced skin tumors in Swiss albinomice. Although studies of single pathways have been helpful in guiding investigations, new tools to study the integrationand multiplicity of signaling pathways hold the hope of improved understanding of the signaling pathway alterationsin cancer chemoprevention by naturally occurring compounds.