1,2,3,4,6-O-五沒食子醯葡萄糖運用於多發性骨髓瘤的治療效果研究

A study of 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranoside in multiple myeloma

Duurenjargal Tseeleesuren(Duurenjargal Tseeleesuren)

指導教授 ： 蕭惠樺

共同指導教授 ： 陳宜民(Yi-Ming Arthur Chen)

高雄醫學大學/醫學院/醫學研究所碩士班/碩士(2016年)

摘要

多發性骨髓瘤(multiple myeloma, MM)是一種血漿內細胞不正常增生(plasma cell neoplasm)的疾病，為血液腫瘤疾病(hematological malignancy)中第二常見。儘管有多種治療方式，多發性骨髓瘤無法被治癒且病患治療的結果大多無法達成預期。因此，新藥物的開發對於治療多發性骨髓瘤具有極大的潛力，天然化合物1,2,3,4,6-O-五沒食子醯葡萄糖 (PGG)已經被發現可抑制多種癌細胞增生並誘發細胞凋亡。此篇論文的目標即是針對PGG做評估是否可作為治療多發性骨髓瘤的新藥物。在多發性骨髓瘤細胞株IM9和RPMI8226中加入PGG然後利用AlamarBlue®方式測定腫瘤細胞的生長情形後，我們發現在細胞株中加入PGG可抑制細胞生長，而隨著時間與濃度增長與增加，抑制效果有明顯的上升。而PGG對於IM9和RPMI8226的IC50分別為8.51和22.5 μg/mL。而在細胞週期的測定中得知，PGG可導致多發性骨髓瘤細胞株停留在G1時期。再來，依據Annexin V陽性的細胞、Caspase 3/7的活性和切割後的Caspase 3蛋白量增加的情形顯示PGG可引起多發性骨髓瘤細胞株內的細胞凋亡。另外，PGG也抑制c-Myc和DEPTOR的基因和蛋白質表現。因此，我們的結果中顯示出PGG具有抑制多發性骨髓瘤的效果，並且提供PGG此化合物未來可被開發使用於治療多發性骨髓瘤的可能性。

關鍵字

多發性骨髓瘤 ； 1,2,3,4,6-O-五沒食子醯葡萄糖

並列摘要

Multiple myeloma (MM), the second most common hematological malignancy is a plasma cell neoplasm. Despite the available treatment options, MM remains an incurable disease and the treatment outcome for patients has not been satisfactory. Therefore, the discovery of novel agents greatly boosts the potential therapeutics for multiple myeloma. The natural compound 1,2,3,4,6-Penta-O-galloyl-beta-D-glucopyranoside (PGG) has been shown to inhibit cellular proliferation and induce apoptosis of various cancer cells. The aim of this study was to evaluate the possibility of PGG as a new therapeutic agent for multiple myeloma. Multiple myeloma cell lines IM9 and RPMI8226 were treated with PGG and tumor cell viability was analyzed using AlamarBlue® assay. We found that PGG inhibits IM9 and RPMI8226 cells growth in dose and time dependent manner with IC50 of 8.51 and 22.5 μg/mL, respectively. Cell cycle analysis in both cell lines revealed that PGG treatment caused cell cycle arrest in G1 phase. In addition, Annexin V positive cells, Caspase 3/7 activity and protein expression level of cleaved caspase 3 was significantly increased by PGG treatment which suggested that PGG induced apoptosis in multiple myeloma cell lines. Moreover, PGG inhibits the mRNA and protein expression of c-Myc and DEPTOR. Altogether, our results demonstrated a growth inhibitory effect of PGG and supported further development of this compound as a new therapeutic agent for treatment of multiple myeloma.

並列關鍵字

Multiple myeloma ； 1,2,3,4,6-Penta-O-galloyl-beta-D-glucopyranoside (PGG)

參考文獻

Abdelwahed, A., Bouhlel, I., Skandrani, I., Valenti, K., Kadri, M., Guiraud, P., Steiman, R., Mariotte, A.M., Ghedira, K., Laporte, F., et al. (2007). Study of antimutagenic and antioxidant activities of gallic acid and 1,2,3,4,6-pentagalloylglucose from Pistacia lentiscus. Confirmation by microarray expression profiling. Chemico-biological interactions 165, 1-13.

Bianchi, G., and Munshi, N.C. (2015). Pathogenesis beyond the cancer clone(s) in multiple myeloma. Blood 125, 3049-3058.

Blade, J., Cibeira, M.T., and Rosinol, L. (2010). Novel drugs for the treatment of multiple myeloma. Haematologica 95, 702-704.

Blade, J., and Rosinol, L. (2008). Advances in therapy of multiple myeloma. Current opinion in oncology 20, 697-704.

Chen, W.J., Chang, C.Y., and Lin, J.K. (2003). Induction of G1 phase arrest in MCF human breast cancer cells by pentagalloylglucose through the down-regulation of CDK4 and CDK2 activities and up-regulation of the CDK inhibitors p27(Kip) and p21(Cip). Biochemical pharmacology 65, 1777-1785.