Role of GDH and PARP inhibitors as novel treatments for SDHB-deficient PPGLs.

Abstract

SDHB, one of the four genes encoding the subunits of the Krebs cycle enzyme succinate dehydrogenase (SDH), acts as a tumor suppressor in several human cancers, including pheochromocytomas/paragangliomas. Mutations in SDHB lead to a reduction or complete loss of enzymatic activity, linking SDHB to paraganglioma malignancy. Given the difficulty in curing metastatic paragangliomas and the limited value of surgery, new treatments are needed. Glutamine dehydrogenase 1 (GDH1), a key regulator of glutathione metabolism, and poly (ADP-ribose) polymerase (PARP), essential for repairing single- or double-stranded DNA breaks, are crucial in cancer initiation and progression. We treated the human pheochromocytoma cell line (hPheo1) with knocked-down SDHB using radiation, the GDH inhibitor 'R162', and the PARP inhibitor 'olaparib'. Combining R162 with radiation enhances anticancer effectiveness, reduces cell proliferation, and causes G2/M phase arrest in the wild-type and KD-SDHB hPheo1 cell line. KD-SDHB hPheo1 cells treated with olaparib alone were more resistant than wild-type cells but were more sensitive in combination with radiation, activated repair mechanisms, and halted cell cycle progression at the G2/M phase. These results suggest that enhancing radiation-induced DNA damage could be a potential treatment strategy for metastatic pheochromocytomas/paragangliomas. Inhibiting GDH1 and PARP activities, with radiation, may represent promising strategies for the treatment of SDHB-deficient pheochromocytoma/paraganglioma; however, their effects do not appear to be specific to SDHB-deficient cells and require further validation.