Anti‐tumor effects of a nonsteroidal anti‐inflammatory drug zaltoprofen on chondrosarcoma via activating peroxisome proliferator‐activated receptor gamma and suppressing matrix metalloproteinase‐2 expression

Higuchi, Takashi; Takeuchi, Akihiko; Yamamoto, Norio; Hayashi, Katsuhiro; Kimura, Hiroaki; Miwa, Shinji; Inatani, Hiroyuki; Shimozaki, Shingo; Kato, Takashi; Aoki, Yu; Abe, Kensaku; Taniguchi, Yuta; Aiba, Hisaki; Murakami, Hideki; Harashima, Ai; Yamamoto, Yasuhiko; Tsuchiya, Hiroyuki

doi:10.1002/cam4.1438

Cited by 24 publications

(15 citation statements)

References 40 publications

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“…Furthermore, a PPARγ ligand can decrease the incidence of nephrotoxicity, which is experienced in 30% of CDDPtreated patients, by reducing TNF-α, a crucial player in CDDP-induced nephrotoxicity (11,12). PIO is a thiazolidinedione derivative and a synthetic PPARγ agonist, which is widely used as an anti-hyperglycemic agent (2,13). In the present study, we found that PIO could inhibit proliferation of osteosarcoma cells in vitro, but not on the osteosarcoma PDOX model when it was administrated alone.…”

Section: Discussionmentioning

confidence: 99%

PPARγ Agonist Pioglitazone in Combination With Cisplatinum Arrests a Chemotherapy-resistant Osteosarcoma PDOX Model

Higuchi¹,

Yamamoto²,

Sugisawa³

et al. 2019

Cancer Genomics Proteomics

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Background/Aim: Cisplatinum (CDDP) is a firstline drug in osteosarcoma treatment and the acquisition of resistance to CDDP is associated with a poor prognosis. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear hormone receptor that plays important roles in cell proliferation, differentiation, development, metabolism and cell death. Recently, PPARγ was reported to enhance the efficacy, overcome resistance, and decrease the toxicity of CDDP in various human cancers. In this study we tested whether pioglitazone (PIO), a PPARγ agonist, could overcome CDDP resistance in osteosarcoma. Materials and Methods: In this study, we used a human osteosarcoma cell line and a patient-derived orthotopic xenograft (PDOX) models of osteosarcoma. We measured cell viability of 143B human osteosarcoma cells when treated with CDDP and PIO. We randomized PDOX models of osteosarcoma into four treatment groups: Group 1, Untreated control; Group 2, PIO alone; Group 3, CDDP alone; Group 4, a combination of CDDP and PIO. Each group comprised six mice. Mice were treated for 14 days and tumor size and body weight were measured. Results: Cell viability of 143B human osteosarcoma cells was significantly reduced when PIO (50 μmol/l) was combined with CDDP compared to CDDP alone. PDOX osteosarcoma tumors treated with the CDDP-PIO combination showed the strongest tumor growth inhibition compared to other treatment groups. PDOX osteosarcoma tumors treated with the CDDP-PIO combination had the least cancer cells and the most necrosis in histological section. Conclusion: These results suggest that combining PIO along with CDDP could be an effective treatment strategy for osteosarcoma and has important clinical potential for patients. Cisplatinum (CDDP) is first-line therapy for osteosarcoma. However, its use is limited due to side-effects, such as nephrotoxicity, neuropathies, and/or bone marrow toxicity (1). Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear hormone receptor superfamily. PPARγ plays important roles in cell proliferation and differentiation, lipid metabolism, development, and cell death and is a candidate tumor suppressor gene (2). PPARγ ligands exert anti-tumor efficacy in various cancer models, however, monotherapy of PPARγ ligands showed a limited efficacy in clinical trials (3). Even though PPARγ ligands are less efficacious as monotherapy, in combination with traditional chemotherapy drugs, they showed improved clinical potential (3). We previously showed that the PPARγ ligand pioglitazone (PIO) could overcome doxorubicin-resistance in an osteosarcoma patient-derived orthotopic xenograft (PDOX) model (4). It has been demonstrated that PPARγ ligands combined with platinum-based drugs increase therapeutic efficacy in multiple cancer models such as nonsmall cell lung cancer (5), colon cancer (6), and ovarian cancer (6), but not in osteosarcoma. In the present study, we tested whether PIO could overcome CDDP-resistance in osteosarcoma PDOX model.

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Section: Discussionmentioning

confidence: 99%

PPARγ Agonist Pioglitazone in Combination With Cisplatinum Arrests a Chemotherapy-resistant Osteosarcoma PDOX Model

Higuchi¹,

Yamamoto²,

Sugisawa³

et al. 2019

Cancer Genomics Proteomics

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“…In all cases, the concentrations we used for the in vivo assays were higher than those used in studies to test the potential of these MMP inhibitors to treat cancer. For instance, ARP has been tested at concentrations of 13 nM and 25 µM [35,36] and CP471474 at 100 nM [37,38]. We did not perform cytotoxicity assays for the evaluated compounds, but all the experiments had negative controls with the inhibitors at the highest tested concentrations.…”

Section: Inhibition Of Hemorrhagic Activitymentioning

confidence: 99%

Potential of Matrix Metalloproteinase Inhibitors for the Treatment of Local Tissue Damage Induced by a Type P-I Snake Venom Metalloproteinase

Preciado

Pereañez

Comer

2019

Toxins

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Snake bite envenoming is a public health problem that was recently included in the list of neglected tropical diseases of the World Health Organization. In the search of new therapies for the treatment of local tissue damage induced by snake venom metalloproteinases (SVMPs), we tested the inhibitory activity of peptidomimetic compounds designed as inhibitors of matrix metalloproteinases on the activities of the SVMP Batx-I, from Bothrops atrox venom. The evaluated compounds show great potential for the inhibition of Batx-I proteolytic, hemorrhagic and edema-forming activities, especially the compound CP471474, a peptidomimetic including a hydroxamate zinc binding group. Molecular dynamics simulations suggest that binding of this compound to the enzyme is mediated by the electrostatic interaction between the hydroxamate group and the zinc cofactor, as well as contacts, mainly hydrophobic, between the side chain of the compound and amino acids located in the substrate binding subsites S1 and S1 ′ . These results show that CP471474 constitutes a promising compound for the development of co-adjuvants to neutralize local tissue damage induced by snake venom metalloproteinases.

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“…Pioglitazone (PIO), a thiazolidinedione derivative, is a potential activator of peroxisome proliferator-activated receptor gamma (PPARγ) (27). (22). A decrease in the chemoresistance of several cancers by activation of PPARγ has been reported (23,24).…”

Section: Patient No 2 Pdox Established From a 14-year-old Patient With Drug-resistant Osteosarcoma Of The Pelvismentioning

confidence: 99%

Osteosarcoma Patient-derived Orthotopic Xenograft (PDOX) Models Used to Identify Novel and Effective Therapeutics: A Review

et al. 2021

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Background/Aim: Recurrent osteosarcoma is recalcitrant with poor response rates to first-line chemotherapy due to heterogeneity and metastatic potential. This disease requires novel drug discovery and precision treatment. Materials and Methods: The osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model mimics the clinical disease and has identified effective clinically-approved drugs and experimental agents, especially drug combinations, that hold much clinical promise. Results: Effective treatment for drugresistant osteosarcoma includes regorafenib, as monotherapy, and temozolomide-irinotecan, trabectedin-irinotecan, sorafenibeverolimus, sorafenib-palbociclib, and olaratumab-doxorubicincisplatinum, as combinations. Conclusion: The PDOX model can be used to improve the outcome of osteosarcoma patients, including individualized, precision therapy. Doxorubicin (DOX), cisplatinum (CDDP), ifosfamide (IFO), and methotrexate (MTX) are first-line therapy for osteosarcoma (1-4). However, osteosarcoma frequently develops resistance to chemotherapy after initial treatment, resulting in tumor recurrence, often metastatic and thereby fatal to the patient (5, 6). Therefore, development of new precision treatment is necessary.The patient-derived orthotopic xenograft (PDOX) model has been developed for sarcoma and mimics the malignant behavior of osteosarcoma due to the natural tumor microenvironment (TME) of the orthotopically-implanted tissue (7-12). Surgical orthotopic implantation (SOI) was used to establish the PDOX models (7-12).The present report reviews the osteosarcoma PDOX models, and their potential to discover effective agents, especially combinations for drug-resistant disease. Patient No. 1. Establishment of a Drug-Resistant Recurrent Osteosarcoma PDOXThe first osteosarcoma PDOX was established from a chondroblastic osteosarcoma of the left distal-femur from a 16-year-old patient who had pre-operative chemotherapy containing CDDP and a limb-salvaging tumor resection with an endoprosthesis (10). One year after the primary surgery, lung metastases were found and metastasectomy was performed. Fresh specimens of the lung metastasis were obtained and immediately taken to our laboratory on wet ice (Figure 1A). The tumor sample was divided into small fragments with surrounding normal tissue in cell-culture medium and subcutaneously implanted on the flank of nude mice (Figure 1B and C). For PDOX establishment, subcutaneous tumors were harvested and divided into 3-4 mm fragments (Figure 1D and E). The vastus-lateralis muscle of the nude mouse was incised and the biceps-femoris muscle was split to expose the distal femur. Subsequently, an incision 5865 This article is freely accessible online.

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Anti‐tumor effects of a nonsteroidal anti‐inflammatory drug zaltoprofen on chondrosarcoma via activating peroxisome proliferator‐activated receptor gamma and suppressing matrix metalloproteinase‐2 expression

Cited by 24 publications

References 40 publications

PPARγ Agonist Pioglitazone in Combination With Cisplatinum Arrests a Chemotherapy-resistant Osteosarcoma PDOX Model

PPARγ Agonist Pioglitazone in Combination With Cisplatinum Arrests a Chemotherapy-resistant Osteosarcoma PDOX Model

Potential of Matrix Metalloproteinase Inhibitors for the Treatment of Local Tissue Damage Induced by a Type P-I Snake Venom Metalloproteinase

Osteosarcoma Patient-derived Orthotopic Xenograft (PDOX) Models Used to Identify Novel and Effective Therapeutics: A Review

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