Pharmacology and preclinical validation of a novel anticancer compound targeting PEPCK-M - 30/11/19
Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.
| pages | 10 |
| Iconographies | 4 |
| Vidéos | 0 |
| Autres | 0 |
Abstract |
Background |
Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate. The mitochondrial isozyme, PEPCK-M is highly expressed in cancer cells, where it plays a role in nutrient stress response. To date, pharmacological strategies to target this pathway have not been pursued.
Methods |
A compound embodying a 3-alkyl-1,8-dibenzylxanthine nucleus (iPEPCK-2), was synthesized and successfully probed in silico on a PEPCK-M structural model. Potency and target engagement in vitro and in vivo were evaluated by kinetic and cellular thermal shift assays (CETSA). The compound and its target were validated in tumor growth models in vitro and in murine xenografts.
Results |
Cross-inhibitory capacity and increased potency as compared to 3-MPA were confirmed in vitro and in vivo. Treatment with iPEPCK-2 inhibited cell growth and survival, especially in poor-nutrient environment, consistent with an impact on colony formation in soft agar. Finally, daily administration of the PEPCK-M inhibitor successfully inhibited tumor growth in two murine xenograft models as compared to vehicle, without weight loss, or any sign of apparent toxicity.
Conclusion |
We conclude that iPEPCK-2 is a compelling anticancer drug targeting PEPCK-M, a hallmark gene product involved in metabolic adaptations of the tumor.
Le texte complet de cet article est disponible en PDF.Abbreviations : PEPCK, 3-MPA, PEP, OAA, MA, GSIS, AARE, ER, CETSA, ITDRF, ADMET, BBB
Keywords : PEPCK-M, Xanthine derivatives, PEPCK inhibitors, Cancer metabolism, Xenograft, Gluconeogenesis, Breast carcinoma, Colon carcinoma, Preclinical, Mitochondrial physiology, CETSA, Insulin secretion
Plan
Vol 121
Article 109601- janvier 2020 Retour au numéro
Article précédent
- Clinical value of ARG1 in acute myocardial infarction patients: Bioinformatics-based approach
- Rui Zhang, Zhenjun Ji, Yangyang Qu, Mingming Yang, Yamin Su, Wenjie Zuo, Qingyou Zhao, Genshan Ma, Yongjun Li
- Inhibiting the expression of anti-apoptotic genes BCL2L1 and MCL1, and apoptosis induction in glioblastoma cells by microRNA-342
- Shokoofeh Ghaemi, Ehsan Arefian, Rezvan Rezazadeh Valojerdi, Masoud Soleimani, Atieh Moradimotlagh, Fatemeh Jamshidi Adegani
Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.
Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’achat d’article à l’unité est indisponible à l’heure actuelle.
Déjà abonné à cette revue ?