Pioglitazone modulates doxorubicin resistance in a in vivo model of drug resistant osteosarcoma xenograft
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ORIGINAL ARTICLE
Pioglitazone modulates doxorubicin resistance in a in vivo model of drug resistant osteosarcoma xenograft Aparna Natarajan 1 & Balaji Ramachandran 1 & Gopal Gopisetty 1 & Subramani Jayavelu 1 & Shirley Sundersingh 2 & Thangarajan Rajkumar 1 Received: 4 May 2020 / Accepted: 24 September 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Osteosarcoma has been reported with treatment failure in up to 40% of cases. Our laboratory had identified genes involved in the PPARγ pathway to be associated with doxorubicin (DOX) resistance. We hence used PPARγ agonist pioglitazone (PIO) to modulate DOX resistance. DOX-resistant cell line (143B-DOX) was developed by gradient exposure to DOX. The cytotoxicity to PIO and in combination with DOX was assayed in vitro, followed by HPLC to estimate the metabolites of PIO in the presence of microsomes (HLMs). Gene expression studies revealed the mechanism behind the cytotoxicity of PIO. Further, the effects were evaluated in mice bearing 143B-DOX tumors treated either with PIO (20 mg/kg/p.o or 40 mg/kg/p.o Q1D) alone or in combination with DOX (0.5 mg/kg/i.p Q2W). 143B-DOX was 50-fold resistant over parental cells. While PIO did not show any activity on its own, the addition of HLMs to the cells in culture showed over 80% cell kill within 24 h, possibly due to the metabolites of PIO as determined by HPLC. In combination with DOX, PIO had shown synergistic activity. Additionally, cytotoxicity assay in the presence of HLMs revealed that PIO on its own showed promising activity compared to its metabolites—hydroxy pioglitazone and keto pioglitazone. In vivo studies demonstrated that treatment with 40 mg/kg/p.o PIO alone showed significant activity, followed by a combination with DOX. Gene expression studies revealed that PIO could modulate drug resistance by downregulating MDR1 and IL8. Our study suggests that PIO can modulate DOX resistance in osteosarcoma cells. Keywords Osteosarcoma . Doxorubicin resistance . Pioglitazone . Pioglitazone metabolites . MDR1 . IL8
Introduction Osteosarcomas (OS) are the most common and highly aggressive malignant primary bone tumor. A higher incidence is seen predominantly in children and during adolescence growth spurt. The risk of developing OS increases due to various inherited conditions and gene instability (Martin et al. 2012; Morrow and Khanna 2015; Rickel et al. 2017). Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00210-020-01982-3) contains supplementary material, which is available to authorized users. * Thangarajan Rajkumar [email protected]; [email protected] 1
Department of Molecular Oncology, Cancer Institute (WIA), Chennai 600036, India
2
Department of Oncopathology, Cancer Institute (WIA), Chennai, India
The advent of intensive neoadjuvant chemotherapy that was pioneered in the 1970s and early 1980s has dramatically improved the cure rate by 60–70% and helped in limb conservation. Doxorubicin (DOX) is the first-line of therapy
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