槲皮素與穀胱甘肽對順鉑抗腫瘤性及副作用之影響的比較

The comparison of the effects of quercetin and glutathione on the antitumor and side effects of cisplatin

林昱芃

指導教授 ： 葉姝蘭

中山醫學大學/健康管理學院/營養學系碩士班/碩士(2024年)

摘要

順鉑 (cisplatin) 是一種常用的臨床化療藥物，但由於其對正常細胞和癌細胞的非選擇性毒性，經常導致副作用產生並限制其使用和療效。研究證實，許多抗氧化植化素或營養素可以減少cisplatin的副作用，例如槲皮素 (quercetin；黃酮類植物化學物質) 和穀胱甘肽 (Glutathione, GSH；人體內重要的抗氧化胜肽)。先前研究指出quercetin 與 cisplatin 合併使用能增強其抑制腫瘤的效果，顯示 quercetin 具有雙相效應，不過其中的機制尚未釐清，而GSH是否亦有此效果並不清楚。
因此，在本研究中，我們首先使用異種移植A549人類肺癌細胞的裸鼠來比較補充quercetin或GSH對給予 cisplatin 治療的裸鼠其腫瘤生長及正常組織傷害的情況。雄性裸鼠右後側背部先給予皮下注射A549細胞，待腫瘤生長2週後，將腫瘤裸鼠隨機分配到以下組別進行8週的實驗：控制組、CDDP組（腹腔注射cisplatin，2.5 mg/kg，每週一次）、CDDP+Q組（腹腔注射quercetin，10 mg/kg，每週三次）、CDDP+LG組（腹腔注射低劑量GSH，100 mg/kg，每週三次）、CDDP+HG組（腹腔注射高劑量GSH，300 mg/kg，每週三次）。結果顯示，與單獨使用cisplatin的組別相比，quercetin顯著增強了cisplatin的抗腫瘤效果，而GSH則未顯示出這種效果。然而，quercetin、LG或HG能恢復由cisplatin引起的最大前肢抓力、器官重量、肌肉損失和睾丸損傷的變化。Quercetin、LG或HG還減少血漿、肝臟、腎臟、肌肉或睾丸中的TNF-α或TBARS升高的趨勢。為了進一步研究造成GSH和quercetin對cisplatin抗腫瘤效果影響差異的機制，我們使用A549細胞進行體外研究。與動物研究一致的,細胞研究顯示GSH有降低cisplatin對A549細胞的細胞毒性之趨勢，而quercetin則顯著增加了cisplatin的毒性，進一步研究的結果顯示，這可能與GSH顯著減少cisplatin誘發的p-p53和p21表現的增加有關，而quercetin則有增加這些蛋白質表現的趨勢，尤其是顯著增加p21表現。
綜上所述，本研究結果顯示quercetin對cisplatin的細胞毒性具有雙相作用，而GSH則非選擇性地同時減少了cisplatin在癌細胞和正常細胞中的細胞毒性，這顯示在化療期間以GSH來改善副作用需要謹慎使用。

關鍵字

順鉑 ； 槲皮素 ； 穀胱甘?

並列摘要

Cisplatin is a commonly used clinical chemotherapeutic drug. However, its nonselective toxicity often results in side effects and limits its use and efficacy. Studies show that many antioxidant phytochemicals or nutrients can reduce the side effects of cisplatin, such as quercetin (a flavonoid phytochemical) and glutathione (GSH, an important antioxidant peptide in the human body). Quercetin has also been shown to enhance cisplatin's antitumor effect, suggesting that quercetin has a biphasic effect. However, the mechanisms remain unclear. In addition, it is not clear whether glutathione has a biphasic effect.
Therefore, in this study, we first used nude mice bearing human lung cancer A549 cells to compare the effects of supplementation of quercetin or glutathione supplementation on tumor growth and normal tissue damage in nude mice exposed to cisplatin. Male nude mice were first injected with A549 cells into the flank for 2 weeks. The tumor-bearing mice were then randomly assigned to the following groups for 8 weeks: Control, CDDP (cisplatin administered by ip, 2.5 mg/kg, once a week), CDDP+ Q (quercetin administered by ip, 10 mg/kg, 3 times/ week), CDDP+LG (GSH administered by ip, 100 mg/kg, 3 times/ week), CDDP+HG (GSH administered by ip, 300 mg/kg, 3 times/ week). The results showed that compared to the cisplatin alone group, quercetin significantly enhanced the antitumor effect of cisplatin, while GSH did not have such an effect. However, quercetin, LG, or HG could restore changes in maximum grip strength, organ weight, muscle loss, and testicular damage induced by cisplatin. Quercetin, LG, or HG also tended to reduce the increase in TNF-α or TBARS in plasma, liver, kidney, muscles, or testes. To investigate the mechanisms by which GSH and quercetin had different effects on the antitumor effect of cisplatin, we used A549 cells to perform an in vitro study. In agreement with the animal study, the cell experiments showed that GSH tended to reduce the cytotoxicity of cisplatin in A549 cells, while quercetin significantly increased the toxicity of cisplatin. Our study suggested that this was related to that GSH significantly reduces the increase in p-p53 and p21 in A549 cells exposed to cisplatin, while quercetin tended to increase the expression of the proteins, especially p21.
Taken together, these results indicate that quercetin has a biphasic effect on the cytotoxicity of cisplatin, whereas GSH nonselectively reduces the toxicity of cisplatin both in cancer and normal cells. Our study indicates the caution needs to be taken in using GSH to improve side effects during chemotherapy.

並列關鍵字

cisplatin ； quercetin ； glutathione

參考文獻

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