ABSTRACT
Adverse side effects of chemotherapy during cancer treatment have shifted considerable focus towards therapies that are not only targeted but are also devoid of toxic side effects. We evaluated the antitumorigenic activity of sulphur, and delineated the molecular mechanisms underlying sulphur-induced apoptosis in non-small cell lung carcinoma (NSCLC) cells. A search for the underlying mechanism revealed that the choice between the two cellular processes, NFκBp65-mediated survival and p53-mediated apoptosis, was decided by the competition for a limited pool of transcriptional coactivator protein p300 in NSCLC cells. In contrast, sulphur inhibited otherwise upregulated survival signaling in NSCLC cells by perturbing the nuclear translocation of p65NFκB, its association with p300 histone acetylase, and subsequent transcription of Bcl-2. Under such anti-survival condition, induction of p53-p300 cross-talk enhanced the transcriptional activity of p53 and intrinsic mitochondrial death cascade. Overall, the findings of this preclinical study clearly delineated the molecular mechanism underlying the apoptogenic effect of the non-toxic homeopathic remedy, sulphur, in NSCLC cells.
Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/metabolism , E1A-Associated p300 Protein/metabolism , Lung Neoplasms/metabolism , NF-kappa B/metabolism , Sulfur/pharmacology , Tumor Suppressor Protein p53/metabolism , Apoptosis , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Cell Line, Tumor , Cell Survival/drug effects , Drug Evaluation, Preclinical , E1A-Associated p300 Protein/genetics , Gene Expression Regulation, Neoplastic/drug effects , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , NF-kappa B/genetics , Signal Transduction/drug effects , Tumor Suppressor Protein p53/geneticsABSTRACT
BACKGROUND: Homoeopathic medicines treat diseases, including cancer, using ultradiluted preparations. Earlier studies indicated that homoeopathic medicines are cytotoxic to tumor cells and reduced animal tumors. However, the mechanism of homoeopathic medicines at the cellular level is not known. METHODS: The following drugs were used in the study: Ruta 200C, Carcinosinum 200C, Hydrastis 200C, Thuja 200C, and Thuja 1M. These drugs were tested for their ability to induce apoptosis as seen by morphology, DNA laddering, expression of genes related to apoptosis, and TUNEL assay. Similarly, the effect of homoeopathic medicines on apoptosis was measured by microarray analysis. Activity of Ruta 200C was compared with that of the mother tincture. RESULTS: Ruta 200C produced morphological changes in the Dalton's lymphoma ascites tumor cells and induced DNA laddering. Carcinosinum 200C increased apoptotic gene p53 and Ruta 200C decreased antiapoptotic gene Bcl2. Administration of potentiated homoeopathic drugs to tumor-bearing mice induced TUNEL-positive cells in the tumor, showing increased apoptosis of tumor cells. Microarray analysis of cells treated with homoeopathic drugs indicated that many enzymes related to apoptosis were increased by homoeopathic drugs. CONCLUSION: These data indicate that apoptosis is one of the mechanisms of tumor reduction of homeopathic drugs. A comparison of potentiated drugs with their mother tincture indicated that the potentiated drugs have biological activity similar to that of their mother tincture in spite of ultradilution.