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Zoledronic Acid Enhanced the Antitumor Effect of Cisplatin on Orthotopic Osteosarcoma by ROS-PI3K/AKT Signaling and Attenuated Osteolysis.

ABSTRACT: Osteoclasts can interact with osteosarcoma to promote the growth of osteosarcoma. Cisplatin is common in adjuvant chemotherapy of osteosarcoma. However, due to chemoresistance, the efficacy is profoundly limited. Previous studies have found that zoledronic acid (ZA) has osteoclast activation inhibition and antitumor effect. However, the combined effect of ZA and cisplatin on osteosarcoma remains unclear. In vitro, the effects of ZA and cisplatin alone or in combination on 143B cell activity, proliferation, apoptosis, and ROS-PI3K/AKT signaling were detected. At the same time, the effect of ZA and cisplatin on osteoclast formation, survival, and activity was detected by TRAP staining and bone plate absorption test. These were further verified in mice. The results showed that in vitro, compared with the single treatment and control, the combination of ZA and cisplatin could significantly inhibit the activity and proliferation of 143B cells and induced their apoptosis and further promoted the generation of ROS and inhibited the phosphorylation of PI3K and AKT. ROS scavenger and the agonist of the PI3K/AKT pathway could reverse these results. In addition, cisplatin in synergy with ZA could significantly inhibit osteoclast formation and survival to reduce bone plate absorption. In vivo, compared with the single group, the tumor volume and cell proliferation were significantly reduced, apoptosis and necrosis of tumor cells increased, and TRAP⁺ osteoclasts and osteolysis destruction decreased in the combined group. In conclusion, ZA enhanced the antitumor effect of cisplatin on osteosarcoma by ROS-PI3K/AKT signaling, reducing the chemoresistance and osteoclast activation to enhance chemotherapy and inhibit osteolysis. And this present study raised the possibility that combining ZA and cisplatin may represent a novel strategy against osteosarcoma.

SUBMITTER: Liu L

PROVIDER: S-EPMC8026287 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundMicroRNAs are short regulatory RNAs that negatively modulate protein expression at a post-transcriptional and/or translational level and are deeply involved in the pathogenesis of several types of cancers. Specifically, microRNA-221 (miR-221) is overexpressed in many human cancers, wherein accumulating evidence indicates that it functions as an oncogene. However, the function of miR-221 in human osteosarcoma has not been totally elucidated. In the present study, the effects of miR-221 on osteosarcoma and the possible mechanism by which miR-221 affected the survival, apoptosis, and cisplatin resistance of osteosarcoma were investigated.Methodology/principal findingsReal-time quantitative PCR analysis revealed miR-221 was significantly upregulated in osteosarcoma cell lines than in osteoblasts. Both human osteosarcoma cell lines SOSP-9607 and MG63 were transfected with miR-221 mimic or inhibitor to regulate miR-221 expression. The effects of miR-221 were then assessed by cell viability, cell cycle analysis, apoptosis assay, and cisplatin resistance assay. In both cells, upregulation of miR-221 induced cell survival and cisplatin resistance and reduced cell apoptosis. In addition, knockdown of miR-221 inhibited cell growth and cisplatin resistance and induced cell apoptosis. Potential target genes of miR-221 were predicted using bioinformatics. Moreover, luciferase reporter assay and western blot confirmed that PTEN was a direct target of miR-221. Furthermore, introduction of PTEN cDNA lacking 3'-UTR or PI3K inhibitor LY294002 abrogated miR-221-induced cisplatin resistance. Finally, both miR-221 and PTEN expression levels in osteosarcoma samples were examined by using real-time quantitative PCR and immunohistochemistry. High miR-221 expression level and inverse correlation between miR-221 and PTEN levels were revealed in osteosarcoma tissues.Conclusions/significanceThese results for the first time demonstrate that upregulation of miR-221 induces the malignant phenotype of human osteosarcoma whereas knockdown of miR-221 reverses this phenotype, suggesting that miR-221 could be a potential target for osteosarcoma treatment.

Project description:BackgroundPancreatic cancer is one of the most aggressive and intractable malignant tumors, and most deaths from pancreatic cancer are related to metastases. It has been demonstrated in vitro that overexpression of programmed death-ligand 1 (PD-L1) correlates with a lack of phosphatase and tensin homologue (PTEN) expression in pancreatic cancer tissue. This loss of PTEN expression may aberrantly activate the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, and thereby promote tumor cell survival, proliferation, and disease progression. In this study, we investigated the potential therapeutic effect of blockading PD-L1 expression on the progression of pancreatic cancer and its spontaneous liver metastases in vivo by inhibiting the PI3K/Akt/mTOR signaling pathway.MethodsWe investigated the effect of blockading PD-L1 in an orthotopic pancreatic cancer mouse model. The pancreatic tumor weights and inhibition ratios were determined after treatment with antimouse PD-L1 antibody for 5 weeks. We used immunohistochemistry methods to investigate PD-L1 expression in pancreatic cancer tissue and spontaneous liver metastasis tissue. The levels of mRNA and protein expression for various components involved in the PI3K/Akt/mTOR signaling pathway as well as for matrix metalloproteinases-2 and -9 (MMP2 and MMP9) were measured by reverse transcription polymerase chain reaction (RT-PCR) and Western blot methods, respectively.ResultsBlockading PD-L1 significantly inhibited tumor growth and decreased the levels of PD-L1 expression in tumor tissue. Furthermore, the levels of PTEN mRNA and protein expression were elevated, while the levels of phospho-Akt (p-Akt) and phospho-mTOR (p-mTOR) protein were decreased in pancreatic cancer and liver metastasis tissues after establishing a PD-L1 blockade. In addition, a PD-L1 blockade decreased the levels of MMP2 and MMP9 mRNA and protein expression in tumor tissues.ConclusionOur results suggest that a blockade of PD-L1 may inhibit the growth and metastasis of pancreatic cancer by modulating the PI3K/Akt/mTOR pathway.

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Zoledronic Acid Enhanced the Antitumor Effect of Cisplatin on Orthotopic Osteosarcoma by ROS-PI3K/AKT Signaling and Attenuated Osteolysis.

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