阿黴素在乳癌治療中是一種相當有效的蒽環類化療藥物;儘管如此,相關的化療副作用相繼出現,其中最常見的副作用即是心臟毒性,此副作用會導致不可逆的生理現象產生,包含肌原纖維的損傷、下降的左心室射出率最後可能導致慢性的心臟衰竭;另外在微觀的細胞恆定上也會出現細胞毒性最後導致細胞走向凋亡。有鑑於阿徽素在乳癌治療上產生的副作用,特別是心臟毒性的產生,本研究擬探討中草藥萃取物黃芩結合阿徽素是否能有效提高乳癌細胞對化療藥物的敏感性,進而在未來治療上提供另一方向的參考。本實驗中細胞凋亡的發生是由於黃芩與阿徽素共同使用下使得細胞內過多的自由基產生,細胞內過多自由基會干擾內質網的恆定系統使得過多的鈣離子被釋放至細胞質和粒線體當中。過多的鈣離子累積於粒線體中會導致粒線體膜電位去極化;Bcl-2 家族能調節去極化的粒線體膜電位藉由釋放粒線體膜間腔的cytochrome c 至細胞質中,而 cytochrome c 接著會在粒線體引起的凋亡路徑中引發一系列
的反應使 cleaved caspase-9 與凋亡體結合進而活化下游caspase-3 最後導致細胞凋亡。另外,在受體配體結合的凋亡路徑中,磷酸化 p38 MAPK 以及磷酸化 ERK 1/2 蛋白可視為合作夥伴,在 DNA 模板中的轉錄調節區間接地調節轉錄因子 NF-κB 在細胞中的表現。細胞內 ROS過
多的情形下,NF-κB 會藉由附著其上 IκB 的降解而活化,因此由細胞質易位至細胞核當中開始其在 DNA 轉錄過程中轉錄調節因子的角色,在轉錄出的 mRNA 中包含了與細胞凋亡相關的Bcl-2 家族成員。根據以上實驗發現,中草藥萃取物黃芩結合阿徽素的抗癌效果在 ROS-ER stress-intrinsic mitochondrial pathway 當中確實可顯著地被提升因此增加癌細胞的化療敏感性導致細胞毒性產生;在未來臨床乳癌治療上更多的機轉還需要再更進一步地研究探討,儘管本實驗仍有許多不足之處,然而或許再治療上可提供輔助上的參考。

Doxorubicin is a powerful anthracycline chemotherapeutic agent for treatment of breast cancer;irrespective of the critical influence towards doxorubicin, some of the side effects are also detected,cardiotoxicity, for paradigm, will lead to an irreversible alteration in physiological system which maybe decreased left ventricular ejection fraction, loss of myofibrils and heart failure as well as in microscopic environment leading to apoptosis in cells. On account of those advance side effects particularly in cardiotoxicity, this study will explore whether the combined treatment of extraction of Chinese herbal medicine, baicalin, on doxorubicin could effectively fascinate or heighten the potential force of chemosensitivity to breast cancer cells. Cellular apoptosis occurs when excessive intracellular ROS is generated, triggered by dual intervention of baicalin and doxorubicin, which disturb the homeostasis in endoplasmic reticulum (ER) resulting to liberation of numerous calcium ion(Ca2+) into cytoplasm and mitochondria. Multitudinous Ca2+ exhibit in mitochondria giving rise to depolarized mitochondrial membrane potential (△Ψm) postdated by modulation of Bcl-2 family membranes prior
to the release of soluble mitochondrial intermembrane proteins(SIMPs) such as cytochrome c succeeded by a series cascade to recruit cleaved-caspase-9 and sequentially activate caspase-3 inducing cell apoptosis via intrinsic pathway. The proteins, phosphorylated p38 MAPK and phospho-ERK 1/2, reside in extrinsic pathway are recognized as cooperators to function on transcriptional
regulation of DNA templet which modulate NF-κB performance obliquely. In the stressful intracellular
environment, NF-κB is activated by degradation of I-κB and translocates into nucleus to conduct gene encoding for apoptosis-required factors, such as Bcl-2 family, which event is linked to intrinsic pathway. Upon the findings in this research, we could demonstrate the effect of baicalin on doxorubicin could enhance cytotoxicity to breast cancer cells via ROS-ER stress-intrinsic mitochondrial pathway and perhaps could lessen the dosage of doxorubicin and explore more of associated mechanism in combined treatment for breast cancer clinic intervention in the future.

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