Human Glioma Cells Therapy Using ATRA-Induced Differentiation Method to Promote the Inhibitive Effect of TMZ and CCDP.

Xinning Li,Zheng Zou,Sizhe Feng,Song Han,Enlong Ma

doi:10.1155/2021/6717582

Abstract

The glioma stem cells (GSCs) performed the self-renewal, proliferation, and differentiation characteristics; their drug resistance has become the main reason for glioma clinical treatment failure. All-trans retinoic acid (ATRA) is an important inducer of cell differentiation, applied in the treatment of hematologic diseases and other solid tumors. ATRA is a fat-soluble compound, which can easily go through the blood-brain barrier. Therefore, in this study, ATRA was used to induce the differentiation of glioma cells and glioma stem cells, reducing the degree of malignancy and improving its chemotherapy resistance. Methods and Treatment. The results of IF and PCR showed that the expression of CD133 was significantly lower than those of undifferentiated cells. Furthermore, temozolomide (TMZ) and cisplatin (CDDP), the first-line drugs, were used for the treatment of GCs and GSCs. The MTT assay results showed that the effect of the combination of the two drugs was significantly stronger than that of one of them alone. Results. Moreover, the MTT assay also demonstrated that TMZ single, CDDP single, and the combination of TMZ and CDDP can inhibit the proliferation of GCs, ATRA-GCs, GSCs, and ATRA-GSCs in a dose- and time-dependent manner; and ATRA-induced differentiation could promote those drugs inhibition effect and increased the chemotherapy sensitivity. Conclusion. Therefore, we successfully purified the suspension spherical glioma stem cells. Moreover, ATRA was demonstrated to induce the differentiation of GCs and GSCs. Furthermore, ATRA-induced differentiation promotes the inhibitive effect of TMZ and CCDP treatment on the proliferation of primary human glioma cells and glioma stem cells, suggesting that ATRA could increase the chemotherapy sensitivity of TMZ and CCDP through inducing cell differentiation. The combination of TMZ and CCDP performed a synergistic role in inhibiting the proliferation of GCs and GSCs.

Highlights

Gliomatosis Cerebri (GC) is one of the most common primary tumors in the central nervous system, accounting for more than 50% of primary intracranial tumors and seriously endangering human life and health [1]. e malignance of GC in WHO classes III and IV accounts for 77.5%, and its 5-year mortality rate is the third highest among systemic cancers after pancreatic cancer and gastric cancer [2]. e main characteristics of GC include infiltrative growth and malignant transformation, leading to the unclear boundary of surrounding brain tissue
To investigate the effect of ATRA on the differentiation of GCs, the results of the MTTassay demonstrated that a lower concentration of ATRA could promote cell proliferation at 24 h and 48 h and produced a weaker inhibition of proliferation after 72 h
Different concentrations of ATRA were used to treat the suspended spherical stem cell-like glioma cells. e results showed that ATRA induces cell differentiation of glioma stem cells (GSCs), a low concentration of ATRA promotes cell proliferation, and a higher concentration of ATRA inhibits cell proliferation (Table 1, Figures 2(a) and 2(b))

Summary

Introduction

Gliomatosis Cerebri (GC) is one of the most common primary tumors in the central nervous system, accounting for more than 50% of primary intracranial tumors and seriously endangering human life and health [1]. e malignance of GC in WHO classes III and IV accounts for 77.5%, and its 5-year mortality rate is the third highest among systemic cancers after pancreatic cancer and gastric cancer [2]. e main characteristics of GC include infiltrative growth and malignant transformation, leading to the unclear boundary of surrounding brain tissue. (1) Temozolomide (TMZ) is one of the most common chemotherapy agents. Erefore, the investigation on effective inhibition of local glioma growth and promoting TMZ drug efficacy is a focal issue in current treatment. ATRA could induce cancer cells to differentiate close to normal cells, restores their lost functions, makes cell less malignant, and increases the sensitivity to chemotherapy drugs. ATRA has immunomodulatory effects, which can promote the proliferation of immune cells and enhance the killing power of immune cells against tumor cells [5]. ATRA is the clinical treatment for acute promyelocytic leukemia (APL), myelodysplasia, and other hematological malignant diseases and has good performance in dermatology, solid tumors, and vascular-related diseases [6]

Methods

Results

Discussion

Conclusion