3-Aryl-2-quinolone derivates were extensively investigated for their inhibition of farnesyl transferase. Taking this as a cue, we studied the other possible mechanism of antitumor activity of 2-quinolone derivates. A series of new 2-quinolone derivatives have been synthesized and screened for their cytotoxicity by trypan blue assay on Ehrlich ascites carcinoma cells and MTT assay on MCF-7 cells. Compound 1a (nJST) was found to be more effective in both studies with the lowest CTC 50 value among all nine synthesized compounds. This compound was further screened on four different cell lines, viz. human breast adenocarcinoma (MCF-7, MDA-MB-231), colon cancer (HCT-15), murine melanoma (B16F10) cell lines for 24 and 48 h. The CTC 50 value of the compound was found to be <10 lM. Compound 1a induced DNA damage which was revealed by DNA fragmentation studies and further confirmed by nuclear staining. The compound also showed significant elevation in Bax and reduction Bcl-2 gene expression levels. Acute toxicity study in mice indicated that the compound is safe till 2000 mg ⁄ kg. Two different doses 50 and 100 mg ⁄ kg were selected and studied in Ehrlich ascites carcinoma model of cancer and have shown significant improvement in survival time and hematological parameters. Treatment for cancer is still being a challenge for medical world. Many researches are going on to get a safe and effective treatment for this disease. 2-Quinolones are one of the molecules in this category. Joseph et al. initiated the exploration of anticancer potential of this moiety by reporting a series of 2-quinolones with 3-aryl and N-alkyl substitutions of which 12 compounds were exhibiting cytotoxicity (CTC 50 ) of more than 10 lM on MCF-7 (human breast cancer) cell line. However, these compounds were found to be nontoxic in in vivo toxicity determination and effective in in vivo model of MXT mouse mammary adenocarcinoma (1).The leading molecule of this category, tipifarnib, is still in clinical trial stage. This molecule is also have 3-aryl and N-methylation substitutions and exhibits cytotoxicity in breast cancer cell lines MDA-MB-231 and BT-474 with a CTC 50 value <30 lM (2). Moreover, it is active orally and causes apoptosis in myeloid leukemia cell line (3).Apoptosis plays a central role in study of carcinogenesis and drug development for the cancer therapy. It is a regulated evolutionary conserved programme of cell suicide. Disturbance in this physiological programme prolongs the life of cell and leads to carcinogenesis. In cancer cells, the apoptosis diminishes and causes dominance of anti-apoptotic protein. Mitochondrial-mediated apoptosis is controlled by anti-apoptotic (Bcl-2) and proapoptotic (Bax and Bad) proteins of Bcl-2 family. Overexpression of Bcl-2 occurs in 40-80% of human breast cancers (4).These studies added rising interest in developing and evaluating anticancer activity of 2-quinolone derivatives through apoptotic pathway. Among quinolones, most of the anticancer compounds have a 3-aryl substitution. However, to our knowl...