XIAP gene downregulation by small interfering RNA inhibits proliferation, induces apoptosis, and reverses the cisplatin resistance of ovarian carcinoma

Ma, Jiajia; Chen, Biliang; Xin, Xiaoyan

doi:10.1016/j.ejogrb.2009.06.011

Cited by 43 publications

(37 citation statements)

References 15 publications

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“…XIAP is extensively expressed in many types of cancer and is not expressed or expressed at a substantially lower level in normal tissue counterparts (10)(11)(12). Accumulating evidence showed that inhibition of XIAP expression using antisense oligonucleotides or small-interfering RNA (siRNA) suppressed tumor cell prolife ration and invasion, induced cell apoptosis, and suppressed tumor growth (13)(14)(15)(16)(17)(18). In addition, Harlin et al reported that XIAP knockout mice are phenotypically normal with no significant pathological characteristics (19).…”

Section: Introductionmentioning

confidence: 99%

“…XIAP is considered one of the most important factors involved in resistance to the apoptotic effects of drugs and radiation in tumor cells (20). It has been shown to be one of the important regulators in cisplatin-and doxorubicin-induced apoptosis in some cancer cells (21,22) and downregulation of XIAP sensitizes cells to cisplatin and doxorubicin (13,23). Therefore, XIAP is considered to be an attractive target with respect to the molecular therapy of cancer.…”

Section: Introductionmentioning

confidence: 99%

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Silencing XIAP suppresses osteosarcoma cell growth, and enhances the sensitivity of osteosarcoma cells to doxorubicin and cisplatin

et al. 2014

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Abstract. X-chromosome-linked inhibitor of apoptosis protein (XIAP) is an important member of the inhibitors of apoptosis (IAP) family. It has been shown that XIAP promotes the invasion, metastasis, growth and survival of malignant cells, and confers resistance to some chemotherapeutic drugs in various types of cancer. However, little is known regarding its detailed role in osteosarcoma (OS). In the present study, we first investigated the expression of XIAP in OS tissues, and an increased expression of XIAP in OS tissues compared to adjacent non-tumor tissue was identified. Additionally, its expression level correlated with key pathological characteristics including clinical stage, tumor size and metastasis. Subsequently, small interfering RNA (siRNA) was used to block XIAP expression to evaluate the effect of XIAP siRNA on cell proliferation, colony formation, cell cycle, apoptosis, tumorigenicity, and the combined effects of doxorubicin or cisplatin in OS cell lines (MG63 cells). Downregulation of XIAP expression using the RNA silencing approach efficiently decreased cell proliferation and colony formation, and induced cell apoptosis and cell cycle in the G0/G1 stage. In addition, this downregulation inhibited tumor growth in a nude murine model. The resuls also showed that treatment with XIAPshRNA in combination with doxorubicin or cisplatin enhanced chemosensitivity. These results suggested that XIAP may aid the diagnosis of OS and may be an effective strategy for gene therapy of this disease.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Silencing XIAP suppresses osteosarcoma cell growth, and enhances the sensitivity of osteosarcoma cells to doxorubicin and cisplatin

et al. 2014

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“…Cisplatin (CDDP) is an effective antitumor agent with a wide range of activity against various human solid tumors ovarian, bladder, cervical, head and neck, esophageal, small cell lung cancer (SCLC) and gastric cancer (15)(16)(17)(18). CDDP was identified to have cytotoxic properties in the 1960s, and earned a place as the key ingredient in the systemic treatment of germ cell cancers by the end of the 1970s.…”

Section: Introductionmentioning

confidence: 99%

Synergistic growth inhibition by sorafenib and cisplatin in human osteosarcoma cells

et al. 2015

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Abstract. Molecular-targeted therapy has shown promise as a treatment for advanced osteosarcoma (OS). Sorafenib (SOR), a multikinase inhibitor, is the approved systemic drug of choice for OS, but has demonstrated limited benefits due to its toxicity and other adverse effects. Therapy strategies for reducing toxicity include using lower doses of SOR in combination with other complementary agents. Cisplatin (CDDP) has been shown to be a promising anticancer drug against various types of cancer including OS. In the present study, SOR was combined with CDDP to determine whether this combinatorial treatment suppressed tumor growth thereby simultaneously reducing doses of the two drugs for the treatment of OS. Human Saos-2 OS cells were treated with SOR and CDDP, alone and in combination, and the effect of these treatments on cell proliferation, colony formation, cell cycle, apoptosis, migration, and invasion, and involvement in receptor signaling, as well as tumor growth ability in nude mice was determined. It was found that the combination of low concentrations of SOR and CDDP significantly suppressed the cell proliferation, colony formation, migration and invasion, and induced cell apoptosis and cell cycle arrest in the G0/G1 stage, and suppressed tumor growth in a nude mouse model compared to the actions of either agent alone. The results also showed that SOR in combination with CDDP significantly suppressed the phosphorylation of extracellular signal-regulated kinase (ERK), which may contribute to the inhibition of tumor growth. These results suggested that SOR in combination with CDDP acts synergistically in the treatment of OS.

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“…It has been showed that XIAP overexpression is correlated with resistance to apoptosis through stimulation of both the intrinsic (mitochondrial-directed) and extrinsic (death receptor-directed) pathways (36,37). Several studies have shown that downregulation of XIAP with siRNA restores chemosensitivity in various tumor cell lines (9)(10)(11)(12)(13)(14). Pan et al showed that the combination of XIAP-shRNA and TRAIL resulted in significant reduction in XIAP expression and potent antitumor activity both in HCC cells and in an animal tumor model (38).…”

Section: Discussionmentioning

confidence: 99%

“…It is highly expressed in various malignancies, while its expression is very low or absent in normal cells, which makes it an attractive target for cancer therapeutics (6)(7)(8). A large number of studies have demonstrated that inhibition of XIAP expression using antisense oligonucleotides or small interfering RNA (siRNA) could suppress the proliferation of tumor cells, induce cell apoptosis, and sensitize tumor cells to chemotherapeutic agents (9)(10)(11)(12)(13)(14). In addition, Harlin et al found that XIAP-knockout mice have normal survival with no significant pathological features, consistent with XIAPtargeted therapeutics exerting minimal toxicity to normal tissues (15).…”

Section: Introductionmentioning

confidence: 93%

Combined treatment of XIAP-targeting shRNA and celecoxib synergistically inhibits the tumor growth of non-small cell lung cancer cells in vitro and in vivo

Zhang

Wang

et al. 2014

Oncology Reports

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Abstract. X-linked inhibitor of apoptosis protein (XIAP) has been shown to be highly expressed in lung cancer, but not in normal lung tissue, which makes it an attractive target for lung cancer treatment. Celecoxib (CXB), a cyclooxygenase-2 inhibitor, is in wide clinical use for the treatment and prevention of non-small cell lung cancer (NSCLC). Therefore, in our study, we combined short hairpin RNA (shRNA) targeted to XIAP (XIAP-shRNA) with CXB and tested the effects of this combination on lung cancer cells to identify more effective therapeutics against lung cancer. An XIAP-shRNA plasmid was constructed and transfected into the A549 NSCLC cell line. The cells were then treated with CXB and XIAP-shRNA alone or in combination for indicated time periods, and the treatments were assessed for their effects on cell proliferation, apoptosis, migration, invasion and receptor signaling using the MTT, TUNEL, wound healing and Matrigel invasion assays and western blotting, respectively. In addition, an NSCLC xenograft model was prepared to observe tumor growth. It was found that both CXB and XIAP-shRNA significantly inhibited cell proliferation, migration and invasion, and induced cell apoptosis in vitro, as well as suppressed tumor growth in vivo. Moreover, the combination of the agents significantly enhanced these effects compared to the single agent treatments. We also found that the combination treatment significantly suppressed constitutive phosphorylation of PI3K and AKT, which may contribute to the inhibition of tumor growth. These findings suggest that the combination of XIAP-shRNA and CXB is a promising drug candidate for the treatment of NSCLC. IntroductionLung cancer is one of the most common neoplasms worldwide, and approximately 85-90% of lung cancer cases are non-small cell lung cancer (NSCLC) (1). Despite the fact that chemotherapy and radiotherapy have been widely used in the treatment of advanced NSCLC, the outcome remains poor, with less than 15% of patients surviving beyond 5 years due to the lack of early diagnosis and effective treatment methods (2,3). Therefore, it is urgent to identify new therapeutics to combat this disease.With the recent advances in the understanding of the molecular pathways involved in NSCLC progression, targeted therapies that are designed to interfere with the mechanisms of cancer cell growth and survival offer new hope in NSCLC therapeutics. X-linked inhibitor of apoptosis protein (XIAP) has been identified as one of the most potent inhibitors of caspases and apoptosis to date and is known to play an important role in cell apoptosis, cell migration and cell invasion (4,5). It is highly expressed in various malignancies, while its expression is very low or absent in normal cells, which makes it an attractive target for cancer therapeutics (6)(7)(8). A large number of studies have demonstrated that inhibition of XIAP expression using antisense oligonucleotides or small interfering RNA (siRNA) could suppress the proliferation of tumor cells, induce cell apoptosis, and sensitiz...

show abstract

XIAP gene downregulation by small interfering RNA inhibits proliferation, induces apoptosis, and reverses the cisplatin resistance of ovarian carcinoma

Cited by 43 publications

References 15 publications

Silencing XIAP suppresses osteosarcoma cell growth, and enhances the sensitivity of osteosarcoma cells to doxorubicin and cisplatin

Silencing XIAP suppresses osteosarcoma cell growth, and enhances the sensitivity of osteosarcoma cells to doxorubicin and cisplatin

Synergistic growth inhibition by sorafenib and cisplatin in human osteosarcoma cells

Combined treatment of XIAP-targeting shRNA and celecoxib synergistically inhibits the tumor growth of non-small cell lung cancer cells in vitro and in vivo

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