Cytokine-induced killer cells induce apoptosis and inhibit the Akt/nuclear factor-κB signaling pathway in cisplatin-resistant human glioma U87MG cells

Abstract

Despite advances in the development of treatment methods, glioma remains among the cancer types with a high rate of mortality. Therefore, significant efforts are made to develop novel strategies for the treatment of glioma. Ineffective, long-term cancer chemotherapy can lead to multidrug resistance (MDR), which is one of the most common reasons for the failure of chemotherapy. The present study investigated the effects of cytokine‑induced killer cells (CIK) on reversing MDR in cisplatin-resistant U87MG cells (U87MG/DDP). Mononuclear cells were isolated from the peripheral blood of healthy individuals and cultured in vitro in the presence of a combination of cytokines to generate CIK for the treatment of U87MG/DDP. An MTS assay, flow cytometric analysis of apoptosis, ELISA, western blotting and reverse transcription quantitative polymerase chain reaction were used to investigate the MDR-reversing effects of CIK as well as the underlying mechanisms. The results showed that cisplatin sensitivity and the apoptotic rate following cisplatin treatment were increased, P‑glycoprotein expression was decreased and the intracellular rhodamine‑123 content was increased in U87MG/DDP co‑cultured with CIK. In addition, the present study also identified increased mRNA and protein expression levels of MDR gene 1 (MDR1), MDR‑associated protein 1 (MRP1), B-cell lymphoma 2, Survivin and glutathione S-transferase‑π, while the phosphorylation of AKT and the transcriptional activity of nuclear factor‑κB in CIK co‑cultured U87MG/DDP was decreased. These results indicated that pre‑treatment with CIK reversed the MDR of U87MG/DDP, and that CIK‑induced apoptosis of U87MG/DDP was associated with the inhibition of Akt/NF‑κB. These findings suggested that treatment with CIK may be an effective method to enhance the sensitivity of patients with glioma to chemotherapy.

Musashi-1 regulates AKT-derived IL-6 autocrinal/paracrinal malignancy and chemoresistance in glioblastoma

“…Since previous reports have indicated the crucial role of active AKT in promoting drug resistance and apoptosis pathway [12, 20, 21], we further studied if AKT activation is essential in MSI1-induced chemoresistance. We inhibited AKT phosphorylation by LY294002 (PI3K inhibitor) and analyzed the protein levels of active caspase-3 and cleaved-PARP by Western blot.…”

The Mechanisms of Current Platinum Anticancer Drug Resistance in the Glioma

“…When cisplatin-resistant U87 cells interact with CIK, the expressions of MDR-1, MRP-1, GST-π, and Bcl-2 are all down-regulated, thus reversing the drug resistance of gliomas. Based on these results, CIK therapy is expected to play a positive role in improving the chemotherapy resistance of glioma patients [ 71 ].…”