探討新穎天然物LHH2-154-1在T細胞急性白血病上的抗癌效果與作用機制

Abstract

血癌不管在台灣或是全球都是一種普遍的癌症，而在血癌中以白血病跟淋巴癌最為常見，在目前白血病的臨床治療以化學療法為最常使用。雖然在近幾年使用化療醫治白血病的五年存活率有上升的趨勢，但一部分晚期的病患往往會出現復發，並伴隨著抗藥性的現象。所以，為白血病研發更有效的治療藥物是當務之急。在本研究，我們透過與衛生福利部國家中藥研究所盧重光教授實驗室的合作，發現從日本琉球女貞的果實內生真菌,phomopsis sp.endo.03261,中純化出的天然物LHH2-154-1，對兩種白血病的細胞株(Jurkat, Sup-T1)有很好的抗癌效果。研究結果顯示，低濃度的LHH2-154-1在Jurkat和Sup-T1細胞中能有效抑制細胞增生、誘導細胞凋亡、並減少細胞的入侵能力。同時，我們也探討LHH2-154-1對癌症重要相關的訊息傳遞路徑(Akt, ERK,mTOR)是否有影響。發現LHH2-154-1能有效減少mTOR下遊蛋白S6和4E-BP1的磷酸化，顯示其抑制mTOR訊息傳遞路徑效果。除此，我們也發現合併使用LHH2-154-1與現有的化療藥物(doxorubicin, etoposide, ciplatin)能加增強它們在Jurkat細胞中的毒殺性。總結以上的研究成果，我們建議LHH2-154-1有潛力成為單獨或合併使用的抗白血病藥物。

Hematologic malignancy is a common cause of cancer deaths in Taiwan and worldwide. While there are many subtypes of hematologic malignancies, lymphomas and leukemia are the two major ones. Although the five-year relative survival rate has risen in recent years, some patients with advanced stages of leukemia may relapse after initial chemotherapy. It is therefore critical to identify relevant molecular targets for developing more effective therapeutic approaches. In this study, with a collaborative effort of Chung-Kuang Lu’s lab (盧重光), we have identified a novel natural anthraquinone derivative from endophytic fungus phomopsis sp.endo032601 in the seed of Ligustrum liukiuense Koidz, LHH2-154-1, as a potent anti-cancer agent. Our results have shown that LHH2-154-1 exhibited potent anti-cancer activities, including repression of cell proliferation and invasion, and induction of apoptosis in T-cell acute lymphoblastic leukemia cell lines (Jurkat, Sup-T1). In addition, we have examined cancer-related critical signaling pathways and found that LHH2-154-1 inhibited mTOR signaling pathway through down-regulating phosphorylation of S6 and 4E-BP1. Furthermore, LHH2-154-1 in combined with current chemo therapeutic agents (doxorubicin, etoposide, ciplatin) exerted enhanced cytotoxicity in Jurkat cells. In conclusion, results from this study suggest that single or combination treatment of LHH2-154-1 is an promising anti-cancer therqpeuatic.