fosbretabulin and Osteosarcoma

This study aimed to investigate the effectiveness of anticancer therapy combining a cytotoxic chemotherapeutic agent, cisplatin (DDP), and a vascular disruptive drug, combretastatin A4 phosphate (CA4P), in osteosarcoma. First, a human osteosarcoma-xenografted mice model was established. Second, the transplanted tumor models were treated with DDP and CA4P in combination or as monotherapy. Third, the therapeutic effects and the mechanism of the drug combination in the inhibition of transplanted tumors was studied. Finally, the toxic effects of the drugs were observed and recorded. The results showed that DDP combined with CA4P significantly inhibited the growth and lung metastasis of transplanted tumors compared with the monotherapy drug group and vehicle control group. Histopathological analysis revealed that apoptotic and necrotic cell death significantly increased in the combination group, and combined treatment significantly inhibited the proliferation of osteosarcoma cells compared with either agent alone or the vehicle control. Additionally, no obvious toxic effects were observed in the combination group. These results indicate that the combined effects of DDP and CA4P on the progression of human osteosarcoma in vivo were superior to that of either agent alone. DDP combined with CA4P exerted synergistic effects at lower concentrations and promoted apoptosis and necrosis, as well as inhibited proliferation of osteosarcoma cells, but it did not increase the systemic toxic effects of chemotherapy. Our findings highlight CA4P as an effective anticancer agent candidate for combination with DDP in clinical applications to treat osteosarcoma.

Topics: Animals; Bone Neoplasms; Cell Line, Tumor; Cisplatin; Humans; Mice; Osteosarcoma; Stilbenes

Combretastatin A-4 (CA-4), a tubulin-depolymerizing agent, shows promising antitumor efficacy and has been under several clinical trials in solid tumors for 10 years. Autophagy has an important pro-survival role in cancer therapy, thus targeting autophagy may improve the efficacy of antitumor agents. N-myc downstream-regulated gene 1 (NDRG1) is a significant stress regulatory gene, which mediates cell survival and chemoresistance. Here we reported that CA-4 could induce cell-protective autophagy, and combination treatment of CA-4 and autophagy inhibitor chloroquine (CQ) exerted synergistic cytotoxic effect on human osteosarcoma (OS) cells. Meanwhile, CA-4 or CQ could increase the expression of NDRG1 independently. We further performed mechanistic study to explore how CA-4 and CQ regulate the expression of NDRG1. Using luciferase reporter assay, we found that CA-4 transcriptionally upregulated NDRG1 expression, whereas CQ triggered colocalization of NDRG1 and lysosome, which subsequently prevented lysosome-dependent degradation of NDRG1. Further, we showed that knockdown of NDRG1 caused the defect of lysosomal function, which accumulated LC3-positive autophagosomes by decreasing their fusion with lysosomes. Moreover, NDRG1 inhibition increased apoptosis in response to combination treatment with CA-4 and CQ. Taken together, our study revealed abrogation of NDRG1 expression sensitizes OS cells to CA-4 by suppression of autophagosome-lysosome fusion. These results provide clues for developing more effective cancer therapeutic strategies by the concomitant treatment with CA-4 and clinical available autophagy inhibitors.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Autophagosomes; Autophagy; Cell Cycle Proteins; Cell Line, Tumor; Chloroquine; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Intracellular Signaling Peptides and Proteins; Lysosomes; Membrane Fusion; Models, Biological; Osteosarcoma; Stilbenes; Up-Regulation

Vascular-targeting agents (VTAs) can be divided into two groups: anti-angiogenesis agents and vascular disrupting agents (VDAs). The purpose of this study was to evaluate the antineoplastic activity of a combination of the anti-angiogenesis agent, Endostar, and the VDA combretastatin, A4 phosphate (CA4P). This study is the first to evaluate the activity of this combination against tumors and the first to investigate the activity of the combination against osteosarcoma. Endostar combined with CA4P had a good anti-tumor effect with no significant toxicity, and was at least not inferior to adriamycin, which is the main drug for osteosarcoma. The use of VDAs combined with anti-angiogenic drugs can result in significantly enhanced anti-tumor effects, providing a novel approach to cancer treatment, which could effectively complement standard treatments. It is believed that this exciting new treatment has the potential to transform the management of cancer.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cell Line, Tumor; Drug Synergism; Endostatins; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Osteosarcoma; Random Allocation; Recombinant Proteins; Stilbenes; Xenograft Model Antitumor Assays