Chemico-Biological Interactions ( IF 4.7 ) Pub Date : 2022-03-10 , DOI: 10.1016/j.cbi.2022.109876 Janaki Ramaiah Mekala 1 , Prasanna Srinivasan Ramalingam 2 , Sivagami Mathavan 3 , Rajesh B R D Yamajala 3 , Nageswara Rao Moparthi 4 , Rohil Kumar Kurappalli 2 , Rajasekhar Reddy Manyam 4
Glioblastoma multiforme (GBM) is a heterogeneous, aggressive brain cancer characterized by chemo-resistance and cancer stemness. Histone deacetylases (HDACs) are a group of enzymes that regulate chromatin epigenetics which were in turn found to be controlled by microRNAs (miRs). The drug employed in chemotherapy for the treatment of GBM is Temozolomide (TMZ). Unfortunately, many GBM patients exhibit chemo-resistance to this drug. Here we have synthesized various Suberoyl anilide hydroxamic acid (SAHA) analogs with many substitutions at the cap site majority of which not yet studied. These SAHA analogs have exhibited profound cytotoxicity at 2 μM, and 4 μM concentrations in GBM cancer cell line U87MG, and 1 μM, and 2 μM concentrations in breast cancer cell line MCF-7. Surprisingly, these analogs have exhibited cytotoxic effects in chronic lymphoid leukemia cells (Raji) at 64 μM, and 128 μM concentrations due to mutated p53. Among all the synthesized analogs 3-Chloro-SAHA, 3-Chloro-4-fluoro SAHA have exhibited effective cytotoxicity in all cancer cells. These potent analogs inhibited HDAC-8 enzyme activity by 2-folds in U87MG, and MCF-7 cell lines and 7-folds decrease in HDAC-8 activity was observed in Raji cell line. These analogs decreased the expression of HDAC-2, HDAC-3 genes and enhanced the expression of p53 tumor suppressor. Interestingly, these compounds decreased the expression of Rictor, the main component of the mTORC2 complex involved cancer cell metabolism. Furthermore, these molecules have decreased oncogenic microRNA expression such as miR-21 and enhanced the expression of tumor suppressor microRNAs such as miR-143. The HDAC binding ability of these molecules was highly significant and have exhibited the ability to cross blood-brain barrier (BBB), and followed the Lipinski rule of five. Thus, these molecules need to be taken up further to clinics for better therapy against GBM either singly or combination therapy.
中文翻译:
帽取代的辛二酰苯胺异羟肟酸类似物的合成、体外和结构方面通过 HDAC/microRNA 调控作为胶质母细胞瘤癌细胞凋亡的潜在诱导剂
多形性胶质母细胞瘤 (GBM) 是一种异质性、侵袭性脑癌,其特征是化学抗性和癌症干性。组蛋白去乙酰化酶 (HDACs) 是一组调节染色质表观遗传学的酶,这些酶又被发现受 microRNAs (miRs) 控制。用于治疗 GBM 的化疗药物是替莫唑胺 (TMZ)。不幸的是,许多 GBM 患者对这种药物表现出化学抗性。在这里,我们合成了各种辛二酰苯胺异羟肟酸 (SAHA) 类似物,在帽位有许多取代,其中大部分尚未研究。这些 SAHA 类似物在 2 μM 和 4 μM 浓度下在 GBM 癌细胞系 U87MG 中以及在 1 μM 和 2 μM 浓度下在乳腺癌细胞系 MCF-7 中表现出深刻的细胞毒性。出奇,由于 p53 突变,这些类似物在 64 μM 和 128 μM 浓度下对慢性淋巴细胞白血病细胞 (Raji) 表现出细胞毒性作用。在所有合成的类似物 3-Chloro-SAHA 中,3-Chloro-4-fluoro SAHA 在所有癌细胞中都表现出有效的细胞毒性。这些有效的类似物在 U87MG 和 MCF-7 细胞系中抑制 HDAC-8 酶活性 2 倍,在 Raji 细胞系中观察到 HDAC-8 活性降低 7 倍。这些类似物降低了HDAC-2、HDAC-3基因的表达并增强了p53肿瘤抑制因子的表达。有趣的是,这些化合物降低了 Rictor 的表达,后者是 mTORC2 复合物的主要成分,涉及癌细胞的代谢。此外,这些分子降低了致癌微小RNA(如miR-21)的表达,并增强了肿瘤抑制微小RNA(如miR-143)的表达。这些分子的HDAC结合能力非常显着,并表现出穿过血脑屏障(BBB)的能力,并遵循Lipinski五规则。因此,这些分子需要进一步应用于临床,以更好地治疗 GBM,无论是单独治疗还是联合治疗。