Abstract
Multidrug resistance (MDR) is a major impediment to cancer treatment. Here, for the first time, we investigated the chemo-sensitizing effect of Noscapine (Nos) at low concentrations in conjunction with docetaxel (DTX) to overcome drug resistance of triple negative breast cancer (TNBC). In vitro experiments showed that Nos significantly inhibited proliferation of TNBC wild type (p < 0.01) and drug resistant (p < 0.05) TNBC cells. Nos followed by DTX treatment notably increased the cell viability (~1.3 fold) markedly (p < 0.05) in 3D models compared to conventional 2D systems. In vivo oral administration of Nos (100 mg/kg) followed by intravenous DTX (5 mg/kg) liposome treatment revealed regression of xenograft tumors in both wild type (p < 0.001) and drug-resistant (p < 0.05) xenografts. In wild type xenografts, combination of Nos plus DTX group showed 5.49 and 3.25 fold reduction in tumor volume compared to Nos and DTX alone groups, respectively. In drug-resistant xenografts, tumor volume was decreased 2.33 and 1.41 fold in xenografts treated with Nos plus DTX significantly (p < 0.05) compared to Nos and DTX alone respectively and downregulated the expression of anti-apoptotic factors and multidrug resistance proteins. Collectively, chemo-sensitizing effect of Nos followed by DTX regime provide a promising chemotherapeutic strategy and its significant role for the treatment of drug-resistant TNBC.
Highlights
According to the American Cancer Society, approximately 246,000 new cases and 40,000 deaths in the United States were reported from breast cancer in 20161
Treatment with Nos alone does not show cytotoxicity of wild type cells but as shown in Fig. 1, cells treated with Nos at low concentrations followed by DTX treatment markedly (p < 0.01) increased the cytotoxicity of wild-type triple negative breast cancer (TNBC) cells
Since caspase 3, cyclin D1, bcl-2 and matrix metallo proteinase 2 (MMP-2) are key regulators in the cell cycle, apoptosis and extracellular matrix, we investigated the protein expression level in treated animal groups (Fig. 4) and full-length blots were included in a supplementary information file as Figures S1 and S2
Summary
According to the American Cancer Society, approximately 246,000 new cases and 40,000 deaths in the United States were reported from breast cancer in 20161. Even though Nos cannot be used as a standalone agent in TNBC treatment, its chemo-sensitizing effect can be critically important for enhancing the tumor specific toxicity of anticancer drugs. To our knowledge there is no report available for low dose oral Nos therapy as chemo-sensitizing agent for taxanes against TNBC. Despite these advances, most of these strategies used alone cannot control and maintain the reversal of the MDR phenomena due to the poor tumor-targeting property of these agents in free forms[19,20]. Kach et al (2014) demonstrated the anti-fibrotic activity of Nos through cAMP/PKA signaling activation mediated by prostaglandin E2 receptors in pulmonary fibroblasts[31]
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