探討Sunitinib對Paclitaxel與Nocodazole在人類乳癌細胞所引發細胞凋亡的影響

Effects of Sunitinib on Paclitaxel and Nocodazole-induced apoptosis in human breast carcinoma cells

邱立婷(Li-Ting Chiu)

指導教授 ： 陳彥州

臺北醫學大學/醫學院/醫學科學研究所/碩士(2011年)

https://doi.org/10.6831/TMU.2011.00032

摘要

Sunitinib (SUT)，是目前臨床上常被用來做為抗血管新生與細胞增生的酪胺酸激酶接受器抑制劑(receptor tyrosine kinase inhibitor，RTKI)類藥物之一。然而，隨著近期不少科學家的研究顯示，SUT與其他化療藥物合併使用可能可以減少使用單一藥物所產生的抗藥性，且可能達到更好的治療癌症效果。故本篇主要是要研究SUT與兩個抗細胞有絲分裂藥物(antimitotic drugs, AMDs)－Paclitaxel (PTX) 與Nocodazole (NOC) ，分別合併使用後對乳癌細胞是否有藥物的協同作用以達到更好的治療效果，並且進一步探討其兩個藥物合併使用所互相影響的分子機轉。而在本篇的研究結果顯示，在人類乳癌細胞株MDA-MB-231，SUT與PTX或與NOC合併使用後，與只使用單一藥物處理組別相比有促進其癌細胞死亡的情形; 然而，在人類乳癌細胞株MCF-7中則發現藥物合併使用後，癌細胞存活率較單獨使用PTX或NOC反而有提升的現象。藉由偵測去氧核醣核酸(DNA)片段化與細胞凋亡(apoptosis)相關蛋白的表現，進一步證實SUT對於在MDA-MB-231與MCF-7兩株細胞株之間有著不同藥物合併的效果。並且也發現在MCF-7細胞株共同使用SUT與PTX或NOC後，會影響原本PTX或NOC所誘導細胞停滯在細胞週期G2/M 時期，而進而降低了細胞走向細胞凋亡，而這樣的結果可能與SUT會干擾抑制G2/M時期調節蛋白的表現有關。在此篇結果顯示，SUT合併使用PTX或NOC在不同種乳癌細胞有不同的治療效果，這樣的發現可以提供做為臨床上治療乳癌患者的參考依據。

關鍵字

sunitinib,paclitaxel,nocodazole,乳癌,細胞凋亡

並列摘要

Sunitinib (SUT), a receptor tyrosine kinase inhibitor, has been used clinically to treat several human cancers such as breast carcinoma, colon carcinoma, and hepatoma. Previous studies showed that combining SUT and clinical chemotherapeutic drugs may reduce the resistance and enhance the antitumor effects of chemotherapeutic drugs. However, some reports indicated that SUT may not possess the activity to enhance, even reduce, the antitumor action of chemotherapeutic agents. In the present study, SUT addition shows distinct effects on the viability of two breast carcinoma cells MDA-MB-231 and MCF-7 in the presence of Paclitaxel (PTX) or Nocodazole (NOC) treatment. PTX or NOC-elicited cytotoxic effects were potentiated by SUT addition in MDA-MB-231 cells; however those effects were inhibited by SUT in MCF-7 cells.Analysis of apoptotic characteristics showed that SUT addition significantly suppressed PTX and NOC-induced DNA ladders, and hypodiploid cells, in MCF-7 cells. Data of the present study may provide evidence to verify the diversified actions of SUT on breast carcinoma cells under anti-tumor agents such as PTX and NOC treatment for further clinical applications.

並列關鍵字

Sunitinib,paclitaxel,nocodazole,breast cancer,apoptosis

參考文獻

2. Chang KJ, Kuo WH, Wang MY. The epidemiology of breast cancer in Taiwan. J. Chinese Oncol. Soc. 2008;24: 85-93

3. Kim JJ, Tannock IF. Repopulation of cancer cells during therapy: an important cause of treatment failure. Nat Rev Cancer 2005; 5: 516-25.

4. Davis AJ, Tannock JF. Epopulation of tumour cells between cycles of chemotherapy: a neglected factor. Lancet Oncol. 2000;1: 86-93.

7. Nakopoulou L, Stefanaki K, Panayotopoulou E, Giannopoulou I, Athanassiadou P, Gakiopoulou-Givalou H, Louvrou A. Expression of the vascular endothelial growth factor receptor-2/flk-1 in breast carcinomas: correlation with proliferation. Hum pathol. 2002;33: 863-870.

9. Seymour L, Dajee D, Bezwoda WR. Tissue platelet derived-growth factor (PDGF) predicts for shortened survival and treatment failure in advanced breast cancer.Breast Cancer Res Treat. 1993;26:247-252.