Scientific and Educational Center "Molecular Bases of Interaction of Microorganisms and Human", World-Class Research Center "Center for Personalized Medicine", Institute of Experimental Medicine, 197376 Saint-Petersburg, Russia.
Department of Pharmacology with a Course in Clinical Pharmacology and Pharmacoeconomics, St. Petersburg State Pediatric Medical University, 194100 Saint-Petersburg, Russia.
Molecules. 2022 Aug 5;27(15):4988. doi: 10.3390/molecules27154988.
Glioblastoma (GBM) is one of the most aggressive and lethal malignancy of the central nervous system. Temozolomide is the standard of care for gliomas, frequently results in resistance to drug and tumor recurrence. Therefore, further research is required for the development of effective drugs in order to guarantee specific treatments to succeed. The aim of current study was to investigate the effects of nerve growth factor (NGF), human cathelicidin (LL-37), protegrin-1 (PG-1), and temozolomide on bioenergetic function of mitochondria, clonogenicity, and migration of human U251 glioma cells. Colony formation assay was used to test the ability of the glioma cells to form colonies in vitro. The U251 glioma cells migration was evaluated using wound-healing assay. To study the mitochondrial metabolism in glioma cells we measured oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) using a Seahorse XF cell Mito stress test kit and Seahorse XF cell Glycolysis stress kit, respectively. We revealed that LL-37, NGF, and TMZ show strong anti-tumorigenic activity on GMB. LL-37 (4 μM), TMZ (155 μM), and NGF (7.55 × 10 μM) inhibited 43.9%-60.3%, 73.5%-81.3%, 66.2% the clonogenicity of glioma U251 cells for 1-2 days, respectively. LL-37 (4 μM), and NGF (7.55 × 10 μM) inhibited the migration of U251 glioma cells on the third and fourth days. TMZ also inhibited the migration of human glioma U251 cells over 1-3 days. In contrast, PG-1 (16 μM) stimulated the migration of U251 glioma cells on the second, fourth, and sixth days. Anti-mitogenic and anti-migration activities of NGF, LL-37, and TMZ maybe are relation to their capacity to reduce the basal OCR, ATP-synthetase, and maximal respiration of mitochondria in human glioma U251 cells. Glycolysis, glycolytic capacity and glycolytic spare in glioma U251 cells haven`t been changed under the effect of NGF, LL-37, PG-1, and TMZ in regard to control level. Thus, LL-37 and NGF inhibit migration and clonogenicity of U251 glioma cells, which may indicate that these compounds have anti-mitogenic and anti-migration effects on human glioma cells. The study of the mechanisms of these effects may contribute in the future to the use of NGF and LL-37 as therapeutic agents for gliomas.
胶质母细胞瘤（GBM）是中枢神经系统中最具侵袭性和致命性的恶性肿瘤之一。替莫唑胺是治疗神经胶质瘤的标准药物，但常导致耐药和肿瘤复发。因此，需要进一步研究开发有效的药物，以保证特定治疗的成功。本研究的目的是研究神经生长因子（NGF）、人源抗菌肽（LL-37）、防御素-1（PG-1）和替莫唑胺对人 U251 神经胶质瘤细胞线粒体生物能功能、集落形成和迁移的影响。采用集落形成实验检测神经胶质瘤细胞在体外形成集落的能力。通过划痕愈合实验评估 U251 神经胶质瘤细胞的迁移能力。为了研究神经胶质瘤细胞中的线粒体代谢，我们使用 Seahorse XF 细胞线粒体应激测试试剂盒和 Seahorse XF 细胞糖酵解应激测试试剂盒分别测量了氧消耗率（OCR）和细胞外酸化率（ECAR）。结果表明，LL-37、NGF 和 TMZ 对 GBM 具有很强的抗肿瘤活性。LL-37（4 μM）、TMZ（155 μM）和 NGF（7.55×10 μM）分别抑制神经胶质瘤 U251 细胞的集落形成 43.9%-60.3%、73.5%-81.3%和 66.2%，作用时间为 1-2 天。LL-37（4 μM）和 NGF（7.55×10 μM）抑制 U251 神经胶质瘤细胞在第 3 天和第 4 天的迁移。TMZ 也抑制了人类神经胶质瘤 U251 细胞在 1-3 天内的迁移。相反，PG-1（16 μM）在第 2、4 和 6 天刺激 U251 神经胶质瘤细胞的迁移。NGF、LL-37 和 TMZ 的抗有丝分裂和抗迁移活性可能与其降低人神经胶质瘤 U251 细胞中线粒体基础 OCR、ATP 合酶和最大呼吸的能力有关。在 NGF、LL-37、PG-1 和 TMZ 的作用下，神经胶质瘤 U251 细胞的糖酵解、糖酵解能力和糖酵解储备均未发生变化。因此，LL-37 和 NGF 抑制 U251 神经胶质瘤细胞的迁移和集落形成，这可能表明这些化合物对人神经胶质瘤细胞具有抗有丝分裂和抗迁移作用。对这些作用机制的研究可能有助于将来将 NGF 和 LL-37 用作神经胶质瘤的治疗药物。
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