補中益氣湯對受放射線傷害之乳癌及幹細胞存活相關因子表現之比較研究

根據之前研究結果指出，漢方補益中藥對於照射放射線後或經化學藥物處理之正常幹細胞/前驅細胞具有保護功效。本實驗目的在探討此補益中藥在保護正常幹細胞的同時，是否同樣可促使受放射線壓力之乳癌細胞死亡。實驗進行上，取 MCF-7、MDA-MB-231 兩乳癌細胞株，乳癌檢體細胞（BCAC）及正常人體間質幹細胞（PLA），在照射放射線（900 ray）前後分別加入250 μg/ml之補中益氣湯 (BY-Tang) 觀察存活細胞數、表面分子及基因、蛋白表現上之變化異同作探討。結果指出，放射線及補中益氣湯處理可促使正常間質幹細胞生長，相對的減少乳癌細胞及乳癌細胞株之存活細胞數。在細胞表面分子之表現上，可以觀察到加入補中益氣湯有降低 MDA-MB-231 早期細胞 AC 133 標誌之比例。其可能相對的減低了癌症幹細胞的存在，減低癌細胞的攻擊性。基因表現上，使用 RT-PCR 及 Real-time PCR array 觀察了前驅細胞基因、細胞週期基因、細胞凋亡基因、致癌基因及腫瘤轉移基因，補中益氣湯會促使 MCF-7 及 MDA-MB-231 之細胞週期抑制基因 P27 及MDA-MB-231細胞修補暨凋亡基因 P53 、 BCAC 之抑制癌細胞生長基因 PNN、BCAC 及 MDA-MB-231 之抑制癌細胞轉移基因 BRMS1、MCF-7 及 MDA-MB-231 之免疫暨發炎基因 CTSL1 的表現量大幅上升，同時抑制 MCF-7 之癌細胞轉移基因 CHD4 表現，但卻不影響 PLA 之基因表現。在 cytokine array 分析上，補中益氣湯會促使 BCAC、MCF-7、MDA-MB-231 之許多免疫相關蛋白（如IL-1α、IL-1β、M-CSF、MDC、MIG、TRAIL-R3）及癌症生長抑制蛋白（如GRO、TNF-α、TIMP-1）表現。因此，顯示補中益氣湯可在不傷害 PLA 的同時，達成輔助抑制乳癌細胞之生長及惡化，特別是在帶有 estrogen receptor 之 MCF-7 上，更有顯著影響，具有輔助癌症病患之功效。

關鍵字

補中益氣湯；乳癌；幹細胞；放射線治療

並列摘要

Previously, we have established a human normal tissue stem/progenitor cell primary culture system to show some traditional Bu-Yi medicine may protect injury and promote recovery of the normal tissue stem/progenitor cells from the chemical or irradiation damages. The objective of this study is to examine whether selective Bu Zong Yi Chi Tang (BY-Tang) may present beneficial pharmacologic effects to normal stem cells but not to malignant cancer cells. We treated BY-Tang on breast cancer primary cell (BCAC), breast cancer cell lines (MCF-7 and MDA-MB-231), and normal mesenchymal stem cell (PLA) under Gamma-ray irradiation stress condition. We found the BY-Tang treatment protected the normal PLA cell survival from the irradiation stress, but not in breast cancer cells, in particular the MCF-7 cells. In cell surface marker analysis, BY-Tang reduced AC133+ sub-population of MDA-MB-231 examined. Heterogeneous influences of oncogenes, tumor suppressor genes, apoptotic genes, early genes by treatment of BY-Tang in three breast cancer cells and normal PLA were observed. Specifically, BY-Tang enhanced the gene expressions of cell cycle inhibitor p27 in MCF-7 and MDA-MB-231, and cell necrotic factor P53 in MDA-MB-231, tumor suppressor PNN in BCAC, metastasis suppressor BRMS1 in MDA-MB-231 and BCAC, and the immune-activator CSTL1 in MCF-7 and MDA-MB-231. And down-regulate tumor metastasis gene CHD4 in MCF-7. But with little influence of PLA. In cytokine array analysis, BY-Tang stimulated immune proteins (e.g. IL-1α, IL-1β, M-CSF, MDC, MIG, TRAIL-R3) and secreted tumor suppressor proteins (e.g. GRO, TNF-α and TIMP1) in BCAC,MCF-7 and MDA-MB-231. Results obtained from this study shows that BY-Tang reacts heterogeneously among the studied cancer cell lines, patient tumor cells, normal PLA stem cells. Estrogen dependent type Breast cancers such as MCF-7, exhibited best effectiveness by the BY-Tang treatment, under the RI stress. Therefore, for better therapeutic efficacy, the BY-Tang medicine may potentially be beneficial to the estrogen dependent type breast cancer irradiation treatment. However, prior to the clinical trials, more in vivo animal study is needed to confirm the cell study results.

並列關鍵字

Bu Zong Yi Chi Tang ； breast cancer ； stem cell ； irradiation therapy

參考文獻

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補中益氣湯對受放射線傷害之乳癌及幹細胞存活相關因子表現之比較研究

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