Investigation of chemoresistance to first-line chemotherapy and its possible association with autophagy in high-risk neuroblastoma

Abstract

High-risk neuroblastoma (NB) is sensitive to chemotherapy but susceptible to chemoresistance. In this study, we aimed to analyze the incidence of chemoresistance in high-risk NB patients and to explore the role of autophagy in NB chemoresistance. We retrospectively analyzed the incidence of changing the chemotherapy regimen due to disease stabilization or disease progression during induction chemotherapy in high-risk NB patients, which was expressed as the chemoresistance rate. The autophagy levels were probed in tumor cells exposed to first-line chemotherapy agents. The sensitivity of tumor cells to chemotherapy agents and apoptosis rate were observed after inhibiting autophagy by transfection of shRNA or chloroquine (CQ). This study included 247 patients with high-risk NB. The chemoresistance rates of patients treated with cyclophosphamide + adriamycin + vincristine (CAV) alternating with etoposide + cisplatin (EP) (Group 1) and CAV alternating with etoposide + ifosfamide + cisplatin (VIP) (Group 2) was 61.5% and 39.9% (P = 0.0009), respectively. Group 2 had better survival rates than group 1. After exposure to cisplatin, cyclophosphamide, and etoposide, the autophagy-related proteins LC3-I, LC3-II, and Beclin-1 were upregulated, and the incidence of autophagy vesicle formation and the expression of P62 were increased. Chemotherapeutic agents combined with CQ significantly increased the chemotherapeutic sensitivity of tumor cells and increased the cell apoptosis. The downregulated expression of Beclin-1 increased the sensitivity of tumor cells to chemotherapeutics. Our results suggest that increasing the chemotherapy intensity can overcome resistance to NB. Inhibition of autophagy is beneficial to increase the sensitivity of NB to chemotherapy agents.

miR-622 Increases miR-30a Expression through Inhibition of Hypoxia-Inducible Factor 1α to Improve Metastasis and Chemoresistance in Human Invasive Breast Cancer Cells

“…Our investigation illustrates that inhibiting miR-30a using an antagomir molecule increases the levels of ATG5 protein to activate LC3-II, which in turn reduces apoptosis and then promotes resistance to docetaxel in MDA-MB-231 cells. These findings are consistent with the results observed in other studies on chemotherapy-resistant cancer cells [20,36,37]. Furthermore, HIF-1α-induced activation of autophagy assumes a pivotal role in liver and bladder cancer cells [9,38].…”

Chloroquine and Chemotherapeutic Compounds in Experimental Cancer Treatment

“…Cisplatin. CQ enhanced the sensitivity to CIS treatment in endometrial adenocarcinoma cells [35], thyroid cancer cell lines (TPC1, ACT1, and KTC1) [41], and SH-SY5Y cells [63]. In all of these cells, CQ effects were associated with the suppression of autophagy accompanied by increased LC3 and p62 expression.…”

Therapy resistance in neuroblastoma: Mechanisms and reversal strategies

“…Inhibition of autophagy by hydroxychloroquine (HCQ) sensitizes NB cells to vincristine ( Belounis et al, 2016 ). Similarly, Chen et al (2022) reported that chemotherapeutic agents including cisplatin, cyclophosphamide, and etoposide combined with chloroquine (CQ) increased the chemotherapeutic sensitivity and cell apoptosis of high-risk NB cells. These facts indicated that autophagy is closely associated with chemoresistance and can be a potential target in the treatment of NB.…”