stilbenes and Nasopharyngeal-Carcinoma

Topics: Antigens, CD; Cadherins; Cell Line, Tumor; Cell Movement; Cell Proliferation; Down-Regulation; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Proteomics; Stilbenes; Vimentin

In this study, we designed biodegradable polymersomes for co-delivery of an antiangiogenic drug combretastatin-A4 phosphate (CA4P) and doxorubicin (DOX) to collapse tumor neovasculature and inhibit cancer cell proliferation with the aim to achieve synergistic antitumor effects. The polymersomes co-encapsulating DOX and CA4P (Ps-DOX-CA4P) were prepared by solvent evaporation method using methoxy poly(ethylene glycol)-b-polylactide (mPEG-PLA) block copolymers as drug carriers. The resulting Ps-DOX-CA4P has vesicles shape with uniform sizes of about 50 nm and controlled co-encapsulation ratios of DOX to CA4P. More importantly, Ps-DOX-CA4P (1:10) showed strong synergistic cytotoxicity (combination index CI = 0.31) against human nasopharyngeal epidermal carcinoma (KB) cells. Furthermore, Ps-DOX-CA4P accumulated remarkably in KB tissues xenografts in nude mice. Consistent with these observations, Ps-DOX-CA4P (1:10) achieved significant antitumor potency because of fast tumor vasculature disruption and sustained tumor cells proliferation inhibition in vivo. The overall findings indicate that co-delivery of an antiangiogenic drug and a chemotherapeutic agent in polymersomes is a potentially promising strategy for cancer therapy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Doxorubicin; Drug Carriers; Drug Combinations; Drug Compounding; Drug Synergism; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Nanocapsules; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Polymers; Stilbenes; Tissue Distribution; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Resveratrol (trans-3,4',5-trihydroxystilbene) has been shown to exert potent anticancer effects on various types of cancer through its anti-proliferative, anti-angiogenic, antioxidant and pro-apoptotic functions. There is still a lack of experimental evidence regarding whether resveratrol has potential anticancer activity in human nasopharyngeal carcinoma (NPC) cells. The purpose of this study was to explore the anticancer activity of resveratrol in human NPC cells both in vitro and in vivo. Our results indicated that treatment with resveratrol led to a time- and dose-dependent decrease in cell proliferation in NPC cells. A dose-dependent increase in apoptosis in response to resveratrol treatment was also observed in NPC cells. Flow cytometric analysis showed that treatment of NPC cells with resveratrol led to cell cycle arrest at the S and G2/M phases. Mechanistically, resveratrol treatment downregulated the expression of Bcl-2 and hypoxia-inducible factor-1α (HIF-1α) proteins and upregulated the expression of caspase-3 protein. In addition, resveratrol treatment also significantly decreased the phosphorylation levels of Akt1, p70S6K and p-4E-BP-1 and the protein expression of several cyclins involved in cell cycle regulation. In vivo studies further showed that resveratrol was able to significantly inhibit the growth of NPC tumor xenografts in nude mice. Collectively, our findings suggest that resveratrol exerts potent anti-prolife-rative and pro-apoptotic effects on human NPC cells possibly through interfering with the pAkt1/p70S6K signaling pathways, thus it may potentially be developed as an effective agent for chemoprevention and chemotherapy of human NPC.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma; Caspase 3; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclins; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mice, Inbred BALB C; Mice, Nude; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neoplasm Transplantation; Phosphorylation; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Resveratrol; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Stilbenes; Xenograft Model Antitumor Assays

Resveratrol, a naturally occurring dietary compound with chemopreventive properties has been reported to trigger a variety of cancer cell types to apoptosis. Whether resveratrol shows any activity on human nasopharyngeal carcinoma (NPC) cells remained to be determined. The aim of this study was to investigate the effect and mechanism of resveratrol on human NPC cells. Treatment of resveratrol resulted in significant decrease in cell viability of NPC cell lines in a dose- and time-dependent manner. A dose-dependent apoptotic cell death was also measured by flow cytometery analysis. Molecular mechanistic studies of apoptosis unraveled resveratrol treatment resulted in a significant loss of mitochondrial transmembrane potential, release of cytochrome c, enhanced expression of Fas ligand (FasL), and suppression of glucose-regulated protein 78 kDa (GRP78). These were followed by activation of caspases-9, -8, -4, and -3, subsequently leading to DNA fragmentation and cell apoptosis. Furthermore, up-regulation of proapoptotic Bax and down-regulation of antiapoptotic Bcl-2 protein were also observed. Taken together, resveratrol induces apoptosis in human NPC cells through regulation of multiple apoptotic pathways, including death receptor, mitochondria, and endoplasmic reticulum (ER) stress. Resveratrol can be developed as an effective compound for human NPC treatment.

Topics: Apoptosis; Carcinoma; Caspases; Cell Line, Tumor; Cell Survival; DNA Fragmentation; Drug Screening Assays, Antitumor; Endoplasmic Reticulum Chaperone BiP; Fas Ligand Protein; Gene Expression Regulation, Neoplastic; Heat-Shock Proteins; Humans; Membrane Potential, Mitochondrial; Models, Biological; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Proto-Oncogene Proteins c-bcl-2; Resveratrol; Signal Transduction; Stilbenes; Transcription Factor CHOP