glutaminase and Bone-Neoplasms

We examined the clinical significance of neoadjuvant chemotherapy (NACT) in limb salvage treatment of osteosarcoma and its effect on the Glutaminase 1 gene (GLS1) expression.. 278 patients admitted to Qianfoshan Hospital Affiliated to Shandong University with osteosarcoma were randomly divided into the study group and the control group. Patients in the study group had 3-4 courses of cisplatin, ifosfamide, and adriamycin (DIA) chemotherapy before surgical excision, while no chemotherapy was used in the control group before the surgery.. GLS1 expression in the study group decreased, the difference showed statistical significance compared with that of the control group (p<0.05). The median survival time of the study group was 48.4±19.7 months while in the control group was 42.4±11.2. The overall survival time of study group was 58.5±15.2 months, which was significantly higher than control 49.4±10.7 (p<0.05). The higher GLS1 expression in osteosarcoma was, the shorter the patients' survival time would be.. Neoadjuvant chemotherapy performed before surgery could significantly decrease the GLS1 expression in osteosarcoma, effectively improving limb salvage treatment of osteosarcoma. The higher the GLS1 expression was, the shorter the patients' survival time would be.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bone Neoplasms; Chemotherapy, Adjuvant; Child; China; Cisplatin; Disease Progression; Disease-Free Survival; Doxorubicin; Female; Glutaminase; Humans; Ifosfamide; Limb Salvage; Male; Middle Aged; Neoadjuvant Therapy; Orthopedic Procedures; Osteosarcoma; Risk Factors; Time Factors; Young Adult

Enchondromas and chondrosarcomas are common cartilage neoplasms that are either benign or malignant, respectively. The majority of these tumors harbor mutations in either IDH1 or IDH2. Glutamine metabolism has been implicated as a critical regulator of tumors with IDH mutations. Using genetic and pharmacological approaches, we demonstrated that glutaminase-mediated glutamine metabolism played distinct roles in enchondromas and chondrosarcomas with IDH1 or IDH2 mutations. Glutamine affected cell differentiation and viability in these tumors differently through different downstream metabolites. During murine enchondroma-like lesion development, glutamine-derived α-ketoglutarate promoted hypertrophic chondrocyte differentiation and regulated chondrocyte proliferation. Deletion of glutaminase in chondrocytes with Idh1 mutation increased the number and size of enchondroma-like lesions. In contrast, pharmacological inhibition of glutaminase in chondrosarcoma xenografts reduced overall tumor burden partially because glutamine-derived non-essential amino acids played an important role in preventing cell apoptosis. This study demonstrates that glutamine metabolism plays different roles in tumor initiation and cancer maintenance. Supplementation of α-ketoglutarate and inhibiting GLS may provide a therapeutic approach to suppress enchondroma and chondrosarcoma tumor growth, respectively. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Topics: Animals; Bone Neoplasms; Cartilage; Chondroma; Chondrosarcoma; Glutaminase; Glutamine; Humans; Isocitrate Dehydrogenase; Ketoglutaric Acids; Mice; Mutation

Chondrosarcoma is a malignant cartilage-forming bone tumour in which mutations in IDH1 and IDH2 frequently occur. Previous studies suggest an increased dependency on glutaminolysis in IDH1/2 mutant cells, which resulted in clinical trials with the drugs CB-839, metformin and chloroquine. In this study, the preclinical rationale for using these drugs as a treatment for chondrosarcoma was evaluated.. Expression of glutaminase was determined in 120 cartilage tumours by immunohistochemistry. Ten chondrosarcoma cell lines were treated with the metabolic compounds CB-849, metformin, phenformin (lipophilic analogue of metformin) and chloroquine.. A difference in glutaminase expression levels between the different tumour grades (p = 0.001, one-way ANOVA) was identified, with the highest expression observed in high-grade chondrosarcomas. Treatment with CB-839, metformin, phenformin or chloroquine revealed that chondrosarcoma cell lines are sensitive to glutaminolysis inhibition. Metformin and phenformin decreased mTOR activity in chondrosarcoma cells, and metformin decreased LC3B-II levels, which is counteracted by chloroquine.. Targeting glutaminolysis with CB-839, metformin, phenformin or chloroquine is a potential therapeutic strategy for a subset of high-grade chondrosarcomas, irrespective of the presence or absence of an IDH1/2 mutation.

Topics: Antineoplastic Agents; Benzeneacetamides; Bone Neoplasms; Chloroquine; Chondrosarcoma; Drug Screening Assays, Antitumor; Glutaminase; Glutamine; Humans; Immunohistochemistry; Isocitrate Dehydrogenase; Metabolic Networks and Pathways; Metformin; Molecular Targeted Therapy; Mutation; Neoplasm Grading; Thiadiazoles; Tumor Cells, Cultured