Combination Treatment With Sorafenib and Everolimus Regresses a Doxorubicin-resistant Osteosarcoma in a PDOX Mouse Model

Higuchi, Takashi; Sugisawa, Norihiko; Miyake, Kentaro; Oshiro, Hiromichi; Yamamoto, Norio; Hayashi, Katsuhiro; Kimura, Hiroaki; Miwa, Shinji; Igarashi, Kentaro; Kline, Zoey; Belt, Paige; Chawla, Sant P.; Bouvet, Michael; Singh, Shree Ram; Tsuchiya, Hiroyuki; Hoffman, Robert M.

doi:10.21873/anticanres.13662

Cited by 21 publications

(29 citation statements)

References 19 publications

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“…We also demonstrated that PDOX models maintain the original histological and molecular characteristics after transplantation in mice (16,17). PDOX models provide osteosarcoma patients with specific and individualized treatment options (18)(19)(20). We previously showed that PIO could overcome doxorubicin resistance in the PDOX model of osteosarcoma (4).…”

Section: Discussionmentioning

confidence: 84%

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: 84%

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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“…Consistently, Everolimus has been proposed as a second-line treatment in osteosarcoma: unluckily, it did not achieve a complete response in patient-derived doxorubicin-resistant osteosarcoma xenografts [47] or in patients with high-grade relapsed osteosarcoma [48] when used alone. The reduction of tumor growth in xenografts and the increase in the progression-free survival of patients was achieved only when Everolimus was combined with Sorafenib [47,48]. These results suggest that targeting only the Akt/mTOR axis is not sufficient to induce a robust anti-tumor effect and/or to chemosensitize refractory osteosarcoma.…”

Section: Discussionmentioning

confidence: 95%

“…As far as drug resistance is concerned, Akt/mTOR induces resistance to doxorubicin, cisplatin, and methotrexate by promoting pro-survival autophagy [46]. Consistently, Everolimus has been proposed as a second-line treatment in osteosarcoma: unluckily, it did not achieve a complete response in patient-derived doxorubicin-resistant osteosarcoma xenografts [47] or in patients with high-grade relapsed osteosarcoma [48] when used alone. The reduction of tumor growth in xenografts and the increase in the progression-free survival of patients was achieved only when Everolimus was combined with Sorafenib [47,48].…”

Section: Discussionmentioning

confidence: 99%

ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma

Belisario

Akman

Godel

et al. 2020

Cells

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The ATP Binding Cassette transporter B1 (ABCB1) induces chemoresistance in osteosarcoma, because it effluxes doxorubicin, reducing the intracellular accumulation, toxicity, and immunogenic cell death induced by the drug. The ATP Binding Cassette transporter A1 (ABCA1) effluxes isopentenyl pyrophosphate (IPP), a strong activator of anti-tumor Vγ9Vδ2 T-cells. Recruiting this population may represent an alternative strategy to rescue doxorubicin efficacy in ABCB1-expressing osteosarcoma. In this work, we analyzed how ABCA1 and ABCB1 are regulated in osteosarcoma, and if increasing the ABCA1-dependent activation of Vγ9Vδ2 T-cells could be an effective strategy against ABCB1-expressing osteosarcoma. We used 2D-cultured doxorubicin-sensitive human U-2OS and Saos-2 cells, their doxorubicin-resistant sublines (U-2OS/DX580 and Saos-2/DX580), and 3D cultures of U-2OS and Saos-2 cells. DX580-sublines and 3D cultures had higher levels of ABCB1 and higher resistance to doxorubicin than parental cells. Surprisingly, they had reduced ABCA1 levels, IPP efflux, and Vγ9Vδ2 T-cell-induced killing. In these chemo-immune-resistant cells, the Ras/Akt/mTOR axis inhibits the ABCA1-transcription induced by Liver X Receptor α (LXRα); Ras/ERK1/2/HIF-1α axis up-regulates ABCB1. Targeting the farnesylation of Ras with self-assembling nanoparticles encapsulating zoledronic acid (NZ) simultaneously inhibited both axes. In humanized mice, NZ reduced the growth of chemo-immune-resistant osteosarcomas, increased intratumor necro-apoptosis, and ABCA1/ABCB1 ratio and Vγ9Vδ2 T-cell infiltration. We suggest that the ABCB1 high ABCA1 low phenotype is indicative of chemo-immune-resistance. We propose aminobisphosphonates as new chemo-immune-sensitizing tools against drug-resistant osteosarcomas.

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“…Athymic nu/nu nude mice (AntiCancer Inc., San Diego, CA, USA), 4-6 weeks old, were used (14)(15)(16)(17)(18)(19)(20). All animal studies were conducted according to an AntiCancer Inc. Institutional Animal Care and Use Committee (IACUC) protocol specifically approved for this study and in accordance with the principles and procedures outlined in the National Institutes of Health Guide for the Care and Use of Animals under Assurance Number A3873-1 (14)(15)(16)(17)(18)(19)(20). In order to minimize any suffering of the animals, anesthesia and analgesics were used for all surgical experiments as previously described (14)(15)(16)(17)(18)(19)(20).…”

Section: Methodsmentioning

confidence: 99%

“…All animal studies were conducted according to an AntiCancer Inc. Institutional Animal Care and Use Committee (IACUC) protocol specifically approved for this study and in accordance with the principles and procedures outlined in the National Institutes of Health Guide for the Care and Use of Animals under Assurance Number A3873-1 (14)(15)(16)(17)(18)(19)(20). In order to minimize any suffering of the animals, anesthesia and analgesics were used for all surgical experiments as previously described (14)(15)(16)(17)(18)(19)(20). Procedures for mouse housing, handling, anesthesia, feeding, and humane endpoint criteria have been previously described (14)(15)(16)(17)(18)(19)(20).…”

Section: Methodsmentioning

confidence: 99%

A Novel Anionic-phosphate-platinum Complex Effectively Targets a Cisplatinum-resistant Osteosarcoma in a Patient-derived Orthotopic Xenograft Mouse Model

Igarashi

Kawaguchi

Yamamoto

et al. 2020

Cancer Genomics Proteomics

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Background/Aim: We have previously developed a novel bone-targeting platinum compound, 3Pt, and showed that it has strong inhibitory activity against osteosarcoma cells and orthotopic cell-line xenograft mouse models. In the present report, we compared the efficacy of 3Pt to cisplatinum (CDDP) in a CDDP-resistant relapsed osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model. Patients and Methods: The tumor of a patient with osteosarcoma of the distal femur was treated with CDDP-based chemotherapy followed by surgery. The surgical specimen was used to establish a PDOX model. An osteosarcoma cell line was also established from the original patient tumor. Osteosarcoma cell viability was assessed with the WST-8 assay and the IC50 values were calculated. The PDOX models were randomized into three groups: untreated control, CDDP-treated group, and 3Pt-treated group. Tumor size and body weight were measured twice a week. Results: 3Pt had a strong concentration-dependent cytocidal effect in vitro. The IC 50 value of 3Pt was significantly lower than that of CDDP. On day 14 of the treatment, 3Pt caused a significantly greater tumor growth inhibition compared to the untreated control and CDDP-treated mice. Conclusion: 3Pt is a promising clinical candidate for the treatment of recalcitrant osteosarcoma. Osteosarcoma is a rare and highly malignant mesenchymal bone tumor. The primary tumor is pathologically characterized by the formation of immature bone or osteoid. A bimodal distribution of osteosarcoma occurence has been reported, with a first peak in adolescence and a second peak in older age (1). Patients with osteosarcoma treated with chemotherapy and surgery have approximately a 70% 5-year survival rate (2-4). First-line chemotherapy for osteosarcoma includes highdose methotrexate (MTX), cisplatinum (CDDP), doxorubicin, (DCX) and ifosfamide (IFS) (5-9). However, dose escalation of these drugs has not been effective for recalcitrant osteosarcoma (6), with 5-year overall survival rates being less than 20% (6-9). We have previously developed a novel platinum complex 3Pt ([Pt(Pt(1R,2R-diaminocyclohexane)(myo-inositol-1,2,3, 4,5,6-hexakisphosphate))2]), which comprises anionic phosphate moieties (10). The cytotoxic potency of 3Pt was higher than that of CDDP in all osteosarcoma cell lines tested. 3Pt was also effective in CDDP-resistant cells (10). Mice treated with 3Pt showed no renal cell injury compared 217 This article is freely accessible online.

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Combination Treatment With Sorafenib and Everolimus Regresses a Doxorubicin-resistant Osteosarcoma in a PDOX Mouse Model

Cited by 21 publications

References 19 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

ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma

A Novel Anionic-phosphate-platinum Complex Effectively Targets a Cisplatinum-resistant Osteosarcoma in a Patient-derived Orthotopic Xenograft Mouse Model

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