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 malignant phenotype. Thus, targeting apoptosis pathways in pre-malignant cells, in which these pathways are still relatively intact, 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 induced tumors in a number of in vivo and in vitro studies. The aberration of tumor suppressor gene, p53 and the ras oncogene have been linked to the induction of multiple signaling pathways and to the resistance offered by cancer cells to the apoptosis. Therefore, the present study was carried out to investigate the role of DAS on modulation of multiple 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 downstream target molecule p21/waf1. Proapoptotic protein, bax was upregulated by DAS supplementation. An opposite trend was observed in DMBA induced antiapoptotic proteins expressions, survivin and bcl-2, which were significantly downregulated by DAS supplementation. In the present study we also demonstrated that DAS supplementation significantly reduces the expression of ras oncoprotein and to modulate expression of its signaling molecules including PI3K/Akt and MAPKs. Western blot analysis demonstrated that DAS significantly reduced the DMBA induced protein expressions of PI3K/Akt and p38MAPK. However, DAS supplementation did not alter the expression JNK1 and ERK1/2. Thus, our results confirm that DAS can adopt a multi-prong strategy to target multiple signaling pathways leading to induction of apoptosis and inhibition of growth of DMBA induced skin tumors in Swiss albino mice. Although studies of single pathways have been helpful in guiding investigations, new tools to study the integration and multiplicity of signaling pathways hold the hope of improved understanding of the signaling pathway alterations in cancer chemoprevention by naturally occurring compounds.