J Jayalakshmi, Vanisree Arambakkam Janardhanam
Department of Biochemistry, University of Madras, Chennai, Tamil Nadu, India.
Ann Neurosci. 2020 Jul;27(3-4):114-123. doi: 10.1177/0972753120950057. Epub 2020 Oct 16.
Glioma, the most common form of a malignant brain tumour is characterised by a poor prognosis, which is attributable to its resistance against current therapeutic approaches. Temozolomide (TMZ), a DNA alkylating agent, is the first-line drug for glioma treatment. Long-term treatment using TMZ was reported to culminate in the development of resistance with overexpression of multidrug resistance 1 gene coded protein P-glycoprotein, which in turn releases the drugs from the tumour cells.
Thus, to circumvent such resistance issues, the current study attempted to explore the effect of naringenin (a flavanone) with proven antiglial tumour potential, in mitigating the features of TMZ resistance.
Colony-forming assay, invasion assay and scratch wound assay were performed among the groups, namely tumour control (C6), vehicle control (V), naringenin (NGEN)-treated, drug-resistant tumour cells (C6R), and drug resistance cells added with NGEN (C6R+NGEN), to examine the impact of NGEN on migration and invasion. The effect of NGEN on filopodia length and density during cell migration was also studied in addition to the matrix metalloproteinases (MMP-2 and MMP-9) and p-ERK levels.
NGEN and C6R+NGEN groups had shown significant reduction ( < .01) in length and density of filopodia, colony formation, invasion and wound healing. Further, NGEN could also modify the assessed protein levels ( < .001), which were involved in migration and invasion in sensitive and resistant cells. Our study had provided the first evidence on NGEN-induced enhanced sensitivity against TMZ resistance with profound influence as an antimigratory and anti-invasive agent.
胶质瘤是恶性脑肿瘤最常见的形式，其预后较差，这归因于它对当前治疗方法具有抗性。替莫唑胺（TMZ）是一种DNA烷化剂，是胶质瘤治疗的一线药物。据报道，长期使用TMZ治疗最终会导致耐药性的产生，多药耐药1基因编码的蛋白P-糖蛋白过度表达，进而将药物从肿瘤细胞中释放出来。
因此，为了规避此类耐药问题，本研究试图探索具有已证实的抗神经胶质瘤潜力的柚皮素（一种黄烷酮）在减轻TMZ耐药特征方面的作用。
在肿瘤对照组（C6）、溶剂对照组（V）、柚皮素（NGEN）处理组、耐药肿瘤细胞组（C6R）以及添加了NGEN的耐药细胞组（C6R+NGEN）之间进行集落形成试验、侵袭试验和划痕试验，以检测NGEN对迁移和侵袭的影响。除了基质金属蛋白酶（MMP-2和MMP-9）以及p-ERK水平外，还研究了NGEN对细胞迁移过程中丝状伪足长度和密度的影响。
NGEN组和C6R+NGEN组在丝状伪足的长度和密度、集落形成、侵袭和伤口愈合方面均显示出显著降低（P<0.01）。此外，NGEN还可以改变所评估的参与敏感和耐药细胞迁移及侵袭的蛋白质水平（P<0.001）。我们（本）研究首次提供了证据，证明NGEN可增强对TMZ耐药的敏感性，并作为一种抗迁移和抗侵袭剂具有深远影响。
