Enhanced Anticancer Activity of Gemcitabine in Combination with Noscapine via Antiangiogenic and Apoptotic Pathway against Non-Small Cell Lung Cancer

Abstract

BackgroundThe aim of this investigation was to evaluate the anticancer activity of Noscapine (Nos) and Gemcitabine (Gem) combination (NGC) against non-small cell lung cancer (NSCLC) and to elucidate the underlying mechanism of action.MethodsIsobolographic method was used to calculate combination index values from cytotoxicity data. In vitro antiangiogenic and apoptotic activity of Nos, Gem and NGC was evaluated. For in vivo studies, female athymic Nu/nu mice were xenografted with H460 tumors and the efficacy of Nos, Gem, or NGC was determined. Protein expressions by immunohistochemical staining were evaluated in harvested tumor tissues.ResultsThe CI values (<0.59) were suggestive of synergistic behavior between Nos and Gem. NGC treatment showed significantly inhibited tube formation and increased percentage of apoptotic cells. NGC, Gem and Nos treatment reduced tumor volume by 82.9±4.5 percent, 39.4±5.8 percent and 34.2±5.7 percent respectively. Specifically, NGC treatment decreased expression cell survival proteins; VEGF, CD31 staining and microvessel density and enhanced DNA fragmentation and cleaved caspase 3 levels compared to single agent treated and control groups.ConclusionNos potentiated the anticancer activity of Gem in an additive to synergistic manner against lung cancer via antiangiogenic and apoptotic pathways. These findings suggest potential benefit for use of NGC chemotherapy for treatment of lung cancer.

Noscapine chemosensitization enhances docetaxel anticancer activity and nanocarrier uptake in triple negative breast cancer

“…Our laboratory and other researchers have provided evidence that enhanced tumor growth inhibition of various tumors was achieved by combining Nos with chemotherapeutic drugs [10,11,17–20]. Further, our group also demonstrated previously that Nos enhances the anticancer activity of doxorubicin in a synergistic manner via inactivation of NF-kB and anti-angiogenic pathways while stimulating apoptosis against TNBC tumors [19]. …”

“…Several studies have suggested that Nos induces multiple proapoptotic responses that induce apoptosis against variety of cancer cells [9,14,15,18]. Previously, our lab also reported the synergistic activity between Nos with cisplatin and gemcitabine in A549 and H460 lung cancer cells [9,19]. The role of Nos as a sensitizer has also been shown by Sung et al (2010) who demonstrated that Nos (50 µM) significantly potentiated the cytotoxic and apoptotic effects of TNF, thalidomide, paclitaxel, and bortezomib in human leukemia KBM-5 cell lines by activating NF-κB [20].…”

Enhanced Anticancer Activity of PF-04691502, a Dual PI3K/mTOR Inhibitor, in Combination With VEGF siRNA Against Non–small-cell Lung Cancer

“…1 Our laboratory is investigating newer combination therapies for lung cancer treatment. 30,31,32 One of the promising treatments for lung cancer are antiangiogenic agents that inhibit tumor growth, proliferation, and metastasis. 7,12 Several signaling molecules governing angiogenesis are of interest, including VEGF and PI3K.…”

“…We have selected human slow growing A549 adenocarcinoma cells and fast growing H460 large-cell carcinoma cells to evaluate the anticancer effect based on our previous studies. 30,31 The A549 and H460 NSCLC cells were obtained from American Type Culture Collection (Rockville, MD). A549 and H460 cells were grown in F12K and RPMI 1640 medium (Sigma Aldrich, St. Louis, MO) supplemented with 10% fetal bovine serum respectively.…”

Effect of citral on the cytotoxicity of doxorubicin in human B-lymphoma cells

“…IC 50 (drug) and IC 50 (citral) are concentrations of each compound when used alone to produce the same effect. CI values are interpreted as follows; CI41.3 antagonism; CI 1.1-1.3 moderate antagonism; CI 0.9-1.1 additive effect; CI 0.8-0.9 slight synergism; CI 0.6-0.8 moderate synergism; CI 0.4-0.6 synergism; CI 0.2-0.4 strong synergism; CI50.1 very strong synergism (Chougule et al, 2011).…”