新穎的小分子化合物之抗癌機制研究

Abstract

轉譯因子NF-кB (nuclear factor kappa-light-chain-enhancer of activated B cells)在許多細胞反應 (如細胞增生、細胞凋亡、免疫及發炎反應) 的調控過程中扮演重要的角色。研究顯示NF-кB調控失常與部分腫瘤細胞的增生有關，且證實透過抑制NF-кB的過度表現，能夠有效地抑制腫瘤細胞的生長，並促進細胞凋亡。因此，轉譯因子NF-кB是一個具潛力的抗癌標靶。交通大學應用化學系孫仲銘教授的實驗室，以2-aminofuran-linked-benzimidazole為核心結構，透過修飾周邊的官能基而衍生出一系列新穎的小分子化合物。經過篩選實驗，我們發現化合物 #1412 (與其衍生物# 21026)，在微摩爾濃度範圍內，具有抗癌的生物活性，且能夠有效地抑制多種癌症細胞株內NF-кB的訊息活化與傳遞。例如，在人類T-淋巴癌細胞株Jurkat 與人類多發性骨髓瘤細胞株RPMI-8226，#1412 (與其衍生物# 21026)藉由抑制TNF-□所活化的IкBα 的磷酸化反應及降解反應，進而抑制NF-кB 成員p65的細胞核遷移活動 ( nuclear translocation )，使NF-кB無法從細胞質進入細胞核內進行目標基因的轉錄反應。另外，#1412 (與其衍生物# 21026)也能夠有效地抑制此二種血液癌症細胞株的增生，並誘導細胞凋亡。總結，此實驗結果建議新穎化合物#1412 (與其衍生物# 21026) 的抗癌效果與其抑制轉譯因子NF-кB訊息傳遞的能力有關。

Transcriptional factor NF-кB plays a critical role in mediating cellular processes, including cellular growth control, apoptosis, immune and inflammatory responses. Dysregulation of the NF-кB signaling pathway has been reported in a variety of cancer types and inhibition of the constitutive NF-кB activity may have therapeutic applications. In this study, we have identified the synthetic compounds #1412 and #21026, novel derivatives of the 2-aminofuran linked benzimidazole (synthesized in the laboratory of Prof. C.M. Sun in the Department of Applied Chemistry at National Chiao Tung University), as potent NF-кB inhibitors. Compound #1412 does- and time-dependently inhibited TNF-α induced NF-кB activation in the low micromolar range in cultured cells. In the human leukemic T cell Jurkat cell line and multiple myeloma RPMI-8226 cell line, both compounds blocked TNF-α induced IкBα phosphorylation and degradation and nuclear translocation of the NF-кB subunit p65. In addition, both compounds affected cell viability and induced cell apoptosis. Taken together, these results suggest that the anticancer activity of compound #1412 and #21026 in human cancer cells is related to inhibition of the NF-кB signaling pathway.