探討新合成HSP90抑制劑MPT0G256誘導細胞凋亡與合併gemcitabine呈現協同作用於人類非小細胞肺癌之體外及體內作用機轉

肺癌不論在全球或是台灣，都位居癌症致死率之首。由於病灶早期不易察覺，確診時常為病灶晚期或已有轉移情形，需要依靠全身性化療藥物或標靶藥物治療。目前的標靶藥物雖然有效提升病患的存活率，但部分病患使用單一機轉標靶藥物後會有抗藥性的產生，使得新機轉藥物的研發是急迫且必須的。. 　　Heat shock protein 90 (HSP90) 是一個molecular chaperone，藉由幫助其受質蛋白 (client proteins) 正確的折疊與增強蛋白質間作用力，使其正常的運作。非小細胞肺癌 (non-small cell lung caner, NSCLC) 中許多的致癌性蛋白是HSP90的受質蛋白，也因此，針對肺癌發展HSP90的抑制劑被認為是有潛力的發展方向。　　MPT0G256是一個全合成的HSP90抑制劑，對於肺腺癌 (adenocarcinoma) 在體外與體內都展現出有效抑制癌細胞生長的作用。首先藉由一系列的篩選，發現MPT0G256能有效抑制人類非小細胞肺癌細胞的增生與毒殺細胞，且能有效抑制HSP90的活性。此外，MPT0G256能藉由降低多種致癌性受質蛋白的表現，抑制多條細胞存活相關的訊息路徑，導致非小細胞肺癌細胞難以存活。而MPT0G256也會導致細胞週期停滯與細胞凋亡。　　接著我們探討併用MPT0G256與其他機轉藥物，如傳統化療藥物gemcitabine於細胞體外的作用。發現MPT0G256併用gemcitabine能協同性地抑制細胞生長，且增強HSP90受質蛋白降解與細胞凋亡情形，同時也測得併用藥物會造成細胞週期的影響。　　接著探討MPT0G256併用gemcitabine於小鼠異體移植實驗的作用。發現單獨使用MPT0G256或gemcitabine都能有效抑制非小細胞肺腺癌的腫瘤生長，併用後呈現出更佳的抑制作用，且能有效降解體內腫瘤組織HSP90受質蛋白表現。　　綜合以上結果，我們認為新合成的HSP90抑制劑MPT0G256具備新藥研發的潛力，且合併gemcitabine治療策略於非小細胞肺癌治療是一個有潛力的發展方向。

關鍵字

HSP90抑制劑；非小細胞肺癌

並列摘要

Lung cancer is the leading cause of cancer death worldwide. Although targeted therapies have led to remarkable improvements in response and survival, some patients will develop acquired drug resistance resulting in disease relapse. Therefore, new drugs with novel mechanisms of anti-cancer therapies are urgently needed to be discovered. 　　Heat shock protein 90 (HSP90) is involved in protein folding and functions as a chaperone for numerous client proteins, many of which are important in non-small cell lung cancer (NSCLC) pathogenesis. MPT0G256 is a novel, fully synthesized HSP90 inhibitor with potent in vitro and in vivo anticancer activity against lung adenocarcinoma. 　　MPT0G256, a novel synthetic HSP90 inhibitor, had shown the best antiproliferative activity and cytotoxicity against human lung adenocarcinoma cells, and it also showed prominent inhibitory effect on HSP90 activity. Moreover, MPT0G256 induced degradation of multiple HSP90 client proteins and thus blocked several cancer survival pathways. In addition, MPT0G256 induced cell cycle arrest and apoptosis in NSCLC cells. 　　We next combined MPT0G256 with gemcitabine in NSCLC cells, and evaluated the drug combinational effect in vitro. Combination of MPT0G256 with both drugs resulted in synergistic growth inhibition, further enhancement of HSP90 client proteins degradation and cell apoptosis over either of the monotherapies in NSCLC cells. Cell cycle analysis after the combined treatment was also performed. 　　Then we evaluated the drug combinational effect in vivo. The combined treatment of MPT0G256 and gemcitabine resulted in more effective tumor growth delay and degradation of HSP90 client proteins than either of monotherapies in NSCLC xenograft models. 　　Together, our results showed that MPT0G256 has great potential as a new drug candidate for targeted therapy or a new strategy in combination with gemcitabine for NSCLC treatment.

並列關鍵字

HSP90 inhibitor ； non-small cell lung cancer

參考文獻

Acquaviva J, Smith DL, Sang J, Friedland JC, He S, Sequeira M, et al. (2012). Targeting KRAS-mutant non-small cell lung cancer with the Hsp90 inhibitor ganetespib. Molecular cancer therapeutics 11(12): 2633-2643.

Google Scholar

Agatsuma T, Ogawa H, Akasaka K, Asai A, Yamashita Y, Mizukami T, et al. (2002). Halohydrin and oxime derivatives of radicicol: synthesis and antitumor activities. Bioorganic medicinal chemistry 10(11): 3445-3454.

Google Scholar

Ahearn IM, Haigis K, Bar-Sagi D, Philips MR (2012). Regulating the regulator: post-translational modification of RAS. Nature reviews. Molecular cell biology 13(1): 39-51.

Google Scholar

Akerfelt M, Morimoto RI, Sistonen L (2010). Heat shock factors: integrators of cell stress, development and lifespan. Nature reviews. Molecular cell biology 11(8): 545-555.

Google Scholar

Alamgeer M, Ganju V, Watkins DN (2013). Novel therapeutic targets in non-small cell lung cancer. Current Opinion in Pharmacology 13(3): 394-401.

Google Scholar

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探討新合成HSP90抑制劑MPT0G256誘導細胞凋亡與合併gemcitabine呈現協同作用於人類非小細胞肺癌之體外及體內作用機轉

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