MPT0E018以及MPT0B002在人類慢性骨髓性白血病細胞及固態瘤之抗腫瘤作用機轉研究

對於癌症的治療，抗藥性(Drug resistance)是目前主要面對的問題，因此為瞭解決此問題研發創新藥物分子是非常重要的。本篇研究主要是探討創新小分子MPT0E018及MPT0B002對於血液腫瘤(如慢性骨髓性白血病; CML)以及固態性腫瘤(如大腸直腸癌以及乳癌)的抗腫瘤效果。MPT0E018及MPT0B002是一種microtubule inhibitor，會促進microtubules進行去聚合化(depolymerization)。藉由MTT Assay分析得知，MPT0E018及MPT0B002可以time- and dose-dependent方式抑制白血病細胞株(K562 IM-sensitive及-resistant)、大腸直腸癌細胞株(colo-205及HT-29)以及乳癌細胞株(MCF-7及MDA-MB231)的增生。MPT0E018及MPT0B002甚至會抑制CML及大腸直腸癌的細胞群落形成的能力以及誘導這三種癌細胞進行細胞凋亡。MPT0E018及MPT0B002會造成K562及IMR細胞的細胞週期停滯在G2/M phase，並且降低Cyclin B1和phospho-Cdc2的表現以及增加phospho-MPM2的表現。同樣地，MPT0E018及MPT0B002也會造成大腸直腸癌細胞的細胞週期停滯在G2/M phase以及增加phospho-MPM2的表現，但是卻增加Cyclin B1的表現。藉由西方墨點法分析結果顯示，MPT0E018及MPT0B002會降低MAPK及Akt的磷酸化，並且活化caspase pathway以及降低Bcl-2、Bcl-xL和Mcl-1的表現量，甚至我們發現MPT0E018及MPT0B002也會降低CML細胞內Bcr-Abl的表現。這些抑制劑也會活化大腸直腸癌細胞的caspase pathway。除此之外，我們發現MPT0E018及MPT0B002在低劑量的情況下，可以抑制乳癌細胞株的轉移的能力，但是不會影響大腸直腸癌細胞。綜合以上實驗結果，創新分子MPT0E018及MPT0B002在不同類型的癌細胞是具有抗腫瘤之效果，因此在未來作為癌症治療藥物具有非常大的潛能。

關鍵字

慢性骨髓性白血病、固態瘤、MPT0E018、MPT0B002

並列摘要

Drug resistance is currently the main problem in cancer therapy, therefore developing novel small molecule inhibitors for chemotherapeutic strategies are very important. The purpose of this study is to identify the anti-tumor effects of novel small molecules, MPT0E018 and MPT0B002, in chronic myeloid leukemia (CML) cells, colorectal cancer cells and breast cancer cells. MPT0E018 and MPT0B002 are microtubule inhibitors that induce microtubule depolymerization in these cancer cells. These inhibitors inhibit the cell proliferation of CML cells (K562 IM-sensitive and -resistant), colorectal cancer cells (HT-29 and colo-205) and breast cancer cells (MCF-7 and MDA-MB231) in time- and dose-dependent manners. At same, MPT0E018 and MPT0B002 inhibit the cell colony formation of CML cells and colorectal cancer cells and induce apoptosis of three types of cancer cells. MPT0E018- and MPT0B002-induced G2/M arrest in K562 and IMR cells were associated with a decrease in cyclin B1 and the phosphorylation of Cdc2, as well as increase in phosphorylation of MPM-2. Similarly, MPT0E018- and MPT0B002-induced G2/M arrest in colorectal cancer cell lines were associated with an increase in cyclin B1 and phosphorylation of MPM-2. Western blot assay showed that MPT0E018 and MPT0B002 decrease the phosphorylation of MAPK and Akt, activate caspase pathway and decrease the levels of Bcl-2, Bcl-xL and Mcl-1 as well as Bcr-Abl in CML cells. These inhibitors also activate caspase pathway in colorectal cancer cell lines. Furthermore, the low dose of MPT0E018 and MPT0B002 inhibit the cell migration of breast cancer cells, but not colorectal cancer cells. Taken together, these results indicate that MPT0E018 and MPT0B002 possess anti-tumor effects that could provide another strategy for treating cancer cells.

並列關鍵字

CML, Solid tumor, MPT0E018, MPT0B002

參考文獻

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MPT0E018以及MPT0B002在人類慢性骨髓性白血病細胞及固態瘤之抗腫瘤作用機轉研究

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