Antitumor Activity of Noscapine in Combination with Doxorubicin in Triple Negative Breast Cancer

The aim of this study was to investigate the anticancer activity and mechanism of action of Noscapine alone and in combination with Doxorubicin against triple negative breast cancer (TNBC).TNBC cells were pretreated with Noscapine or Doxorubicin or combination and combination index values were calculated using isobolographic method. Apoptosis was assessed by TUNEL staining. Female athymic Nu/nu mice were xenografted with MDA-MB-231 cells and the efficacy of Noscapine, Doxorubicin and combination was determined. Protein expression, immunohistochemical staining were evaluated in harvested tumor tissues. values of 36.16±3.76 and 42.7±4.3 µM respectively. The CI values (<0.59) were suggestive of strong synergistic interaction between Noscapine and Doxorubicin and combination treatment showed significant increase in apoptotic cells. Noscapine showed dose dependent reduction in the tumor volumes at a dose of 150–550 mg/kg/day compared to controls. Noscapine (300 mg/kg), Doxorubicin (1.5 mg/kg) and combination treatment reduced tumor volume by 39.4±5.8, 34.2±5.7 and 82.9±4.5 percent respectively and showed decreased expression of NF-KB pathway proteins, VEGF, cell survival, and increased expression of apoptotic and growth inhibitory proteins compared to single-agent treatment and control groups.Noscapine potentiated the anticancer activity of Doxorubicin in a synergistic manner against TNBC tumors via inactivation of NF-KB and anti-angiogenic pathways while stimulating apoptosis. These findings suggest potential benefit for use of oral Noscapine and Doxorubicin combination therapy for treatment of more aggressive TNBC

Enhancement of Docetaxel Anticancer Activity by a Novel Diindolylmethane Compound in Human Non-Small Cell Lung Cancer

PURPOSE: This study was conducted to examine the cytotoxic effects of a peroxisome proliferator-activated receptor γ (PPARγ) agonist, 1,1-bis (3′ indolyl)-1-(p-biphenyl) methane (DIM-C-pPhC(6)H(5)) alone and in combination with docetaxel (doc) in vitro in A549 lung cancer cells and in vivo in nude mice bearing A549 orthotopic lung tumors. EXPERIMENTAL DESIGN: Isobolographic method was used to calculate combination index (CI) values from cell viability data. Apoptosis was evaluated in A549 cells by terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay and measurement of cleaved PARP level. Expression of proteins was studied by Western blotting. A549 cells were implanted to induce orthotopic lung tumors in nude mice and the efficacy of doc, DIM-C-pPhC(6)H(5), or combination was determined. Apoptosis and cleaved caspase-3 expression in the harvested tissues were studied by TUNEL and immunohistochemistry, respectively. RESULTS: The CI values (0.36 to 0.9) suggested synergistic to additive effects of doc plus DIM-C-pPhC(6)H(5) and resulted in the highest increase in percentage of apoptotic cells, expression of cleaved PARP, Bax, and N-cadherin compared to treatment with either agent. The combination also enhanced procaspase-3 and -9 cleavage. In vivo, doc + DIM-C-pPhC(6)H(5) reduced lung weights by 57% compared to 39 % by doc, or 22% by DIM-C-pPhC(6)H(5) alone, induced apoptosis in 43 % of the tumor cells compared to 29 % and 22 % in tumors treated with doc and DIM-C-pPhC(6)H(5), respectively, and increased procaspase-3 cleavage compared to either agent alone. CONCLUSIONS: These findings suggest potential benefit for use of doc and DIM-C-pPhC(6)H(5) combination in lung cancer treatment