Carnosic acid potentiates the anticancer effect of temozolomide by inducing apoptosis and autophagy in glioma

• Published in: Journal of neuro-oncology 2019-01, Vol.141 (2), p.277-288
• Main Authors: Shao, Naiyuan, Mao, Jiahao, Xue, Lian, Wang, Rong, Zhi, Feng, Lan, Qing
• Format: Article
• Language: English
• Subjects: Abietanes - administration & dosage; AKT protein; Antineoplastic Agents, Alkylating - administration & dosage; Antioxidants; Apoptosis; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; Brain cancer; Brain Neoplasms - drug therapy; Brain tumors; Cancer; Caspase; Caspase-3; Cell adhesion & migration; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Cell survival; Cell Survival - drug effects; Cholecystokinin; Colonies; Cyclin B1; Cytotoxicity; Drug Synergism; Flow cytometry; Glioma; Glioma - drug therapy; Glioma cells; Humans; Immunofluorescence; Laboratory Investigation; Medical prognosis; Medicine; Medicine & Public Health; Neurology; Oncology; Phagocytosis; Poly(ADP-ribose) polymerase; Temozolomide; Temozolomide - administration & dosage; Wound healing
• ISSN: 0167-594X; 1573-7373; 1573-7373
• DOI: 10.1007/s11060-018-03043-5

Objective Malignant glioma is a lethal brain tumor with a low survival rate and poor prognosis. New strategies are urgently needed to augment the chemotherapeutic effects of temozolomide (TMZ), the standard drug in glioma treatment. Carnosic acid (CA) has been reported to have anticancer, antioxidant and anti-infectious properties. In this study, we aimed to investigate the anticancer effects and the underlying mechanisms of CA in combination with TMZ in glioma cancer cells. Methods The glioma cancer cells were treated with TMZ, CA, or TMZ + CA. We evaluated cell survival by CCK-8 assay, cell anchorage-independent survival by colony formation assay, cell migration by wound-healing assay, cell cycle and cell apoptosis by flow cytometry, and protein expression by western blot. Results CA enhanced the cytotoxic effect of TMZ in glioma cancer cells. CA enhanced TMZ-induced inhibition of colony formation and cell migration and enhanced TMZ-induced cell cycle arrest and cellular apoptosis. Immunofluorescence suggested that CA in combination with TMZ triggered autophagy. Furthermore, CA promoted TMZ-induced cell cycle arrest and cellular apoptosis by Cyclin B1 inhibition and activation of PARP and Caspase-3, while CA promoted TMZ-induced cellular autophagy by p-AKT inhibition, p62 downregulation and LC3-I to LC3-II transition. Conclusion These data suggest that the combination therapy of CA and TMZ strengthens the anticancer effect of TMZ by enhancing apoptosis and autophagy.