Curcumin potentiates the potent antitumor activity of ACNU against glioblastoma by suppressing the PI3K/AKT and NF-κB/COX-2 signaling pathways

Jun Zhao,1,* Jiabin Zhu,2,* Xiaoshu Lv,3 Jinshan Xing,4 Shuang Liu,5 Chen Chen,6 Yinghui Xu1 1Department of Neurosurgery, 2Department of Urology, First Affiliated Hospital of Dalian Medical University, 3Department of Endocrinology, 4Department of Neurosurgery, 5Department of Gastroenterology, Second Affiliated Hospital of Dalian Medical University, 6Department of Cardiovascular, First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China *These authors contributed equally to this work Abstract: Glioblastoma (GBM) is a highly invasive and challenging primary tumor of the central nervous system (CNS), and currently available treatments provide limited benefits to patients with this disease. Therefore, the development of novel therapeutic targets and effective treatment strategies is essential. Nimustine hydrochloride (ACNU) is widely used as the standard chemotherapeutic agent and is frequently administered together with other chemotherapeutic agents in clinical studies. Curcumin, a natural polyphenolic compound, could potentially be combined with chemotherapeutics for cancer treatment; however, there are no reports of studies where ACNU and curcumin were combined for GBM treatment, and the mechanisms underlying their activity remain poorly understood. In the present study, we investigated the effects of combined treatment with curcumin and ACNU on GBM cells and found that it significantly enhanced the inhibition of cell proliferation, colony formation, migration, and invasion. In addition, co-treatment with curcumin increased ACNU-induced apoptosis through enhancing the release of cytochrome c from the mitochondrial intermembrane space into the cytosol. Further, curcumin and ACNU acted synergistically in their antitumor effects by targeting N-cadherin/MMP2/9, PI3K/AKT, and NF-κB/COX-2 signaling. These results indicate that curcumin can enhance the anti-proliferation, anti-migration, and proapoptotic activities of ACNU against GBM, and provide strong evidence that combined treatment with curcumin and ACNU has the potential to be an effective therapeutic option for GBM. Keywords: turmeric, nimustine, cell proliferation, apoptosis, combined modality therapy