sepantronium and Osteosarcoma

Reportedly, the elevated expression of survivin has been observed in several tumor types, strictly involved in tumor development. In the present study, we detected elevated survivin expression in tumor tissues derived from patients with chemoresistant osteosarcoma when compared with those from chemosensitive patients. Importantly, knockdown of survivin in osteosarcoma cells significantly suppressed cell proliferation and chemoresistance both in vitro and in vivo. Simultaneously, chemotherapy mediates the upregulation of survivin in osteosarcoma cells through a survivin-based selective killing effect, resulting in the development of multidrug resistance. The utilization of tumor-derived microparticles to coencapsulate the survivin inhibitor YM155 and chemotherapeutic agents could effectively reverse multidrug resistance, leading to improved anticancer effects, as well as reduced systemic toxicity. In summary, the expression of survivin contributes to resistance toward osteosarcoma drugs, whereas employing survivin inhibiting combination therapy, based on a microparticle codelivery system, could efficiently reverse resistance and avoid potential systemic toxicity.

Topics: Animals; Cell Line, Tumor; Cell Survival; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Imidazoles; Mice; Mice, Inbred BALB C; Naphthoquinones; Osteosarcoma; Survivin

Canine osteosarcoma (OSA) is an aggressive and highly malignant primary bone tumor. Its poor survival outcome remains problematic despite recent advances in anti-cancer therapy, therefore highlighting the need for alternative treatment options or drug repositioning. The aim of this study was to determine if YM155, a small-molecule survivin inhibitor, potentiates the chemotherapeutic efficacy of etoposide against canine OSA in vitro and in vivo. In cell culture, YM155 enhanced the cytotoxic effect of etoposide against canine OSA cell lines; however, the molecular mechanism behind this effect was heterogeneous, as only one cell line had an elevated apoptotic level. In addition, this effect was not associated with survivin suppression in two of the cell lines. These results suggest that the molecular target of YM155 is not restricted to survivin alone. When tested on a murine xenograft model, the average tumor volume of the combination treatment group (YM155, 5 mg/kg, intraperitoneally, 5 consecutive days/week; and etoposide, 20 mg/kg, intraperitoneally, every 5 days) was 66% smaller than the control group, although this difference was not statistically significant (P=0.17). Further studies to improve the treatment protocol are necessary to confirm the findings of this study.

Topics: Animals; Antineoplastic Agents; Apoptosis; Bone Neoplasms; Cell Proliferation; Dog Diseases; Dogs; Drug Synergism; Etoposide; Humans; Imidazoles; Mice; Naphthoquinones; Osteosarcoma; Survivin; Xenograft Model Antitumor Assays

Survivin is an important oncogenic protein expressed highly in osteosarcoma. Here, we have shown that small molecule inhibitor YM155 potently suppressed survivin expression, inhibited cell growth, and induced apoptosis in osteosarcoma cells. Furthermore, we also showed that knock down of survivin by small interfering RNA strongly inhibited cell viability in two osteosarcoma cell lines, suggesting that suppression of survivin essentially contributes to YM155-mediated anticancer activity in osteosarcoma cells. Collectively, our study suggests that YM155 holds promise for patients with osteosarcoma.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Naphthoquinones; Osteosarcoma; Survivin; Tumor Stem Cell Assay

YM155, a novel small-molecule inhibitor of survivin, is known to exert antitumor effects on various cancers, including breast, prostate and lung cancer. However, there are few studies describing the inhibitory effect of YM155 on human osteosarcoma (OS) which highly expresses survivin. Here, we tested the effects of YM155 on OS cells by several in vitro experiments. It was found that YM155 inhibited cell proliferation, colony formation, migration and invasion, induced cell apoptosis, as well as increased caspase-3, -8 and -9 activity in the OS cell lines in a dose-dependent manner. We also found that YM155 suppressed Mcl-1 and survivin expression without affecting the expression of anti-apoptotic proteins X-linked inhibitor of apoptosis (XIAP) and Bcl-2. In addition, YM155 decreased phosphoinositide 3-kinase (PI3K) and AKT expression without effecting total PI3K and AKT in the OS cell lines, which contributed to suppression of OS tumor growth at least in part. In addition, YM155 also suppressed tumor growth in vivo, reducing the size of OS MG63 cell xenografts. Taken together, the findings revealed that YM155 suppresses the tumor growth of OS in vitro and in vivo, suggesting that YM155 has potential as a therapeutic agent for the treatment of OS.

Topics: Animals; Antineoplastic Agents; Bone Neoplasms; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Male; Mice; Naphthoquinones; Osteosarcoma; Xenograft Model Antitumor Assays

Chemoresistance is the principal reason for poor survival and disease recurrence in osteosarcoma patients. Survivin, a family member of the inhibitor of apoptosis proteins, plays an important role in inhibition of apoptosis. Survivin is expressed in a vast majority of human cancers, which is often correlated with poor prognosis in a wide variety of cancer patients. Furthermore, survivin expression is often related with chemoresistance in cancer cells, including osteosarcoma (OS). Here, we evaluated the therapeutic potential of YM155, a selective survivin suppressant alone and in combination with cisplatin using human OS models.. U-2 OS, SW1353, MG-63 cells were treated with YM155, and/or cisplatin, and cell viability, apoptosis, survivin protein expression levels were then evaluated. Furthermore, the efficacy of YM155 combined with cisplatin was further examined in established xenograft models.. YM155 was sufficient to induce spontaneous apoptosis of OS cells. Combination with YM155 significantly augmented the cytotoxicity of cisplatin in OS cells. Combination treatment of YM155 and cisplatin showed antiproliferative effects and induced a greater rate of apoptosis than the sum of the single-treatment rates and promoted tumor regression in established OS xenograft models.. Our findings provide evidence that YM155 could act as a survivin inhibitor on OS cells. Chemotherapeutic approaches using YM155 might enhance the benefit of the cisplatin in the treatment of OS cells. YM155 could be further developed as a potential therapeutic agent for the treatment of OS.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bone Neoplasms; Cell Line, Tumor; Cell Survival; Cisplatin; Drug Resistance, Neoplasm; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Mice; Mice, Inbred ICR; Models, Animal; Naphthoquinones; Neoplasm Recurrence, Local; Osteosarcoma; Survivin; Xenograft Model Antitumor Assays