Zoledronic acid in combination with serine/threonine phosphatase inhibitors induces enhanced cytotoxicity and apoptosis in hormone‐refractory prostate cancer cell lines by decreasing the activities of PP1 and PP2A

Cirak, Yalcin; Varol, Umut; Atmaca, Harika; Kısım, Aslı; Sezgin, Canfeza; Karabulut, Bülent; Uzunoğlu, Selim; Uslu, Rüçhan; Karaca, Burçak

doi:10.1111/j.1464-410x.2012.11392.x

Cited by 15 publications

(11 citation statements)

References 31 publications

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“…However, PP2A inhibitors have also shown benefit for cancer treatment in certain conditions. For instance, PP2A inhibition has been shown to induce apoptosis in T leukemia cells, pancreatic cancer, and prostate cancer (11,(40)(41)(42), and gene therapy strategy targeting PP2A has shown efficacy on HCC in vitro and in vivo (43). In addition, endothall, another PP2A inhibitor, even showed that growth inhibition preferentially inhibited HCC cell lines compared with normal fetal hepatocytes (44).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Protein Phosphatase 2A Enhances Cytotoxicity and Accessibility of Chemotherapeutic Drugs to Hepatocellular Carcinomas

Bai

Zhang

et al. 2014

Molecular Cancer Therapeutics

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Hepatocellular carcinoma (HCC) is one of the most common and therapeutically challenging malignancies worldwide. For patients ineligible for "curative resection" or liver transplantation, chemotherapy is an important minimally effective option. Strategies for chemosensitization are urgently needed. Here, we report that LB-100, a serine/threonine protein phosphatase 2A (PP2A) inhibitor, enhances the cytotoxicity of chemotherapy for HCC in vitro and in vivo. We found that LB

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Section: Discussionmentioning

confidence: 99%

Inhibition of Protein Phosphatase 2A Enhances Cytotoxicity and Accessibility of Chemotherapeutic Drugs to Hepatocellular Carcinomas

Bai

Zhang

et al. 2014

Molecular Cancer Therapeutics

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“…The reason, why the delay of SREs does not results in improved survival, is unclear. A couple of preclinical studies have shown direct anticancer effects of bisphosphonates on PC cells [ 37 ] and indicate an important role of the mevalonate pathway in the biology of PC [ 38 ]. Moreover, studies showing that the mortality of men with hip fractures is as high as 38% within one year after fracture raise expectations that SRE prevention may result in improved survival [ 39 ].…”

Section: Bone Targeted Therapies For Prevention Of Skeletal Relatementioning

confidence: 99%

Targeting Bone Metabolism in Patients with Advanced Prostate Cancer: Current Options and Controversies

Todenhöfer

Stenzl²,

Hofbauer

et al. 2015

International Journal of Endocrinology

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Maintaining bone health remains a clinical challenge in patients with prostate cancer (PC) who are at risk of developing metastatic bone disease and increased bone loss due to hormone ablation therapy. In patients with cancer-treatment induced bone loss (CTIBL), antiresorptive agents have been shown to improve bone mineral density (BMD) and to reduce the risk of fractures. For patients with bone metastases, both zoledronic acid and denosumab delay skeletal related events (SREs) in the castration resistant stage of disease. Novel agents targeting the Wnt inhibitors dickkopf-1 and sclerostin are currently under investigation for the treatment of osteoporosis and malignant bone disease. New antineoplastic drugs such as abiraterone, enzalutamide, and Radium-223 are capable of further delaying SREs in patients with advanced PC. The benefit of antiresorptive treatment for patients with castration sensitive PC appears to be limited. Recent trials on the use of zoledronic acid for the prevention of bone metastases failed to be successful, whereas denosumab delayed the occurrence of bone metastases by a median of 4.1 months. Currently, the use of antiresorptive drugs to prevent bone metastases still remains a field of controversies and further trials are needed to identify patient subgroups that may profit from early therapy.

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“…Moreover, the endogenous protein Cancer Inhibitor of PP2A (CIP2A) has been reported to be highly expressed and involved in PCa progression via c-MYC regulation [ 9 , 10 ], and CIP2A knockdown is able to resensitize metastatic castration-resistant PCa cells to cabazitaxel [ 11 ]. However, contradictory results about the potential therapeutic value of PP2A activation in PCa have been reported to date [ 12 , 13 , 14 , 15 , 16 ]. Whereas some studies support the antitumor properties derived from PP2A activation of compounds such as sodium selenate, ceramide, or carnosic acid [ 12 , 13 , 14 ], others highlight that PP2A inhibition led to anticancer effects [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Activation of the Tumor Suppressor PP2A Emerges as a Potential Therapeutic Strategy for Treating Prostate Cancer

et al. 2015

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Protein phosphatase 2A (PP2A) is a tumor suppressor complex that has recently been reported as a novel and highly relevant molecular target in prostate cancer (PCa). However, its potential therapeutic value remains to be fully clarified. We treated PC-3 and LNCaP cell lines with the PP2A activators forskolin and FTY720 alone or combined with the PP2A inhibitor okadaic acid. We examined PP2A activity, cell growth, prostasphere formation, levels of PP2A phosphorylation, CIP2A and SET expression, and AKT and ERK activation. Interestingly, both forskolin and FTY720 dephosphorylated and activated PP2A, impairing proliferation and prostasphere formation and inducing changes in AKT and ERK phosphorylation. Moreover, FTY720 led to reduced CIP2A levels. Treatment with okadaic acid impaired PP2A activation thus demonstrating the antitumoral PP2A-dependent mechanism of action of both forskolin and FTY720. Levels of PP2A phosphorylation together with SET and CIP2A protein expression were studied in 24 PCa patients and both were associated with high Gleason scores and presence of metastatic disease. Altogether, our results suggest that PP2A inhibition could be involved in PCa progression, and the use of PP2A-activating drugs might represent a novel alternative therapeutic strategy for treating PCa patients.

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Zoledronic acid in combination with serine/threonine phosphatase inhibitors induces enhanced cytotoxicity and apoptosis in hormone‐refractory prostate cancer cell lines by decreasing the activities of PP1 and PP2A

Cited by 15 publications

References 31 publications

Inhibition of Protein Phosphatase 2A Enhances Cytotoxicity and Accessibility of Chemotherapeutic Drugs to Hepatocellular Carcinomas

Inhibition of Protein Phosphatase 2A Enhances Cytotoxicity and Accessibility of Chemotherapeutic Drugs to Hepatocellular Carcinomas

Targeting Bone Metabolism in Patients with Advanced Prostate Cancer: Current Options and Controversies

Activation of the Tumor Suppressor PP2A Emerges as a Potential Therapeutic Strategy for Treating Prostate Cancer

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