Abstract
Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. The present study investigated the expression of Cytochrome P-450 (CYP) genes: CYP1A2, CYP3A4 and CYP3A5 by qRT-PCR in 135 specimens obtained from OS patients, including biopsy (pre-chemotherapy), tumor resected in surgery (post-chemotherapy), adjacent bone to tumor (nonmalignant tissue), pulmonary metastasis and adjacent lung to metastasis (nonmalignant tissue). Normal bone and normal lung tissues were used as control. We also investigated in five OS cell lines the modulation of CYPs expression by cisplatin, doxorubicin and methotrexate. As result, the adjacent lung specimens presented CYP1A2 overexpression compared to the normal lung (p=0.0256). Biopsy specimens presented lower CYP3A4 expression than normal bone (p=0.0314). The overexpression of both CYP1A2 and CYP3A4 in post-chemotherapy specimens were correlated with better event free-survival (p=0.0244) and good response (p=0.0484), respectively. Furthermore, in vitro assays revealed that CYP1A2 was upregulated by doxorubicin (p=0.0034); CYP3A4 was upregulated by cisplatin, doxorubicin and methotrexate (p=0.0004, p=0.0024, p<0.0001, respectively); and CYP3A5 was downregulated by doxorubicin (p=0.0285) and upregulated in time-dependent manner by methotrexate (p=0.0239). In conclusion, our findings suggest that CYP genes play an important role in OS tumorigenesis, at primary and metastatic sites, as well in treatment response.
Highlights
Osteosarcoma (OS) originates from primitive mesenchymal cells and it is the most common malignant bone tumor in children and adolescents [1]
The present study investigated the expression of Cytochrome P-450 (CYP) genes: CYP1A2, CYP3A4 and CYP3A5 by quantitative reverse transcription PCR (qRT-PCR) in 135 specimens obtained from OS patients, including biopsy, tumor resected in surgery, adjacent bone to tumor, pulmonary metastasis and adjacent lung to metastasis
Many CYP members detoxify anticancer drugs used in OS treatment, such as ifosfamide, doxorubicin, etoposide and cisplatin [5, 6], the impact of CYP to treatment response and prognosis in OS needs to be further explored and defined [5]
Summary
Osteosarcoma (OS) originates from primitive mesenchymal cells and it is the most common malignant bone tumor in children and adolescents [1]. OS treatment still uses the same drugs since 1980s and survival rates have not been improved since translational research is required to identify targets for novel treatment modalities [2]. The CYP enzymes mediate metabolic activation of procarcinogens, they could play a role in both tumorigenesis and treatment response [4]. Many CYP members detoxify anticancer drugs used in OS treatment, such as ifosfamide, doxorubicin, etoposide and cisplatin [5, 6], the impact of CYP to treatment response and prognosis in OS needs to be further explored and defined [5]. Mensah-Osman et al verified that Pregnane Xenobiotic Receptor (PXR) plays a critical role in CYP3A4 gene expression regulation in OS and its activation may influence the chemotherapy effect in target genes implicating drug resistance [10]. Analyses of CYP3A4/5 expression in OS biopsies revealed that high expression might predict metastasis and poor prognosis in OS [7]
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