Bortezomib-induced Apoptosis in the Treatment of Non-small Cell Lung Cancer

Bortezomib引發細胞凋亡在非小細胞肺癌治療之應用

楊聰明(Tsung-Ming Yang) ； Dario Barbone ； V. Courtney Broaddus

《內科學誌》 20卷2期 (2009/04) Pp. 106-119

https://doi.org/10.6314/JIMT.2009.20(2).02

摘要

雖然癌症化學治療藥物在過去十數年間有顯著進步，非小細胞肺癌的化學治療卻仍沒有令人滿意的療效，而且常伴隨著明顯的藥物副作用。目前有許多標靶治療藥物被研究於治療癌症，其中蛋白解體抑制劑(proteasome inhibitor)被發現可以導致許多腫瘤細胞株發生細胞凋亡(apoptosis)。Bortezomib (Velcade)是第一個進入臨床試驗的蛋白解體抑制劑，由於對多發性骨髓瘤療效顯著，因此已被核准用於治療多發性骨髓瘤。實驗也發現單獨使用Bortezomib或同時合併其他標靶或化學治療藥物可引發肺癌細胞株發生顯著的細胞凋亡，故Bortezomib也進入臨床試驗治療非小細胞肺癌，但這些臨床試驗結果卻不如預期中理想。本文中我們描述蛋白解體在細胞恆定及細胞凋亡機轉中的角色、Bortezomib導致癌細胞株發生細胞凋亡的機轉、以及在非小細胞肺癌臨床試驗之療效，並進一步探討Bortezomib在非小細胞肺癌臨床試驗療效不如預期的可能原因、以及未來如何改善其療效之可能研究方向。

並列摘要

Despite advances in the past few decades, current chemotherapy regimens have had only limited efficacy with modest survival benefit and significant toxicity in non-small cell lung cancer (NSCLC) patients. Novel therapies, especially those targeting cell signaling pathways, are now under extensive investigation against many tumor types. Proteasome inhibition, one of the novel cancer therapies, has been shown to have widespread ability to induce apoptosis in vitro in a broad spectrum of tumor cell lines. Bortezomib (Velcade) is the first proteasome inhibitor to enter clinical trials. It has demonstrated encouraging efficacy against multiple myeloma, where it is now an approved therapy. In in vitro studies of lung cancer, bortezomib has been found to induce marked apoptosis by itself or when used together with other novel therapy agents or chemotherapy agents. Despite these promising results, bortezomib has not shown great efficacy against lung cancer in clinical trials. In this review, we describe the role of the proteasome in cell homeostasis and apoptosis, the molecular mechanisms of bortezomib-induced apoptosis in preclinical studies of NSCLC cells, and its efficacy to date in the clinical trials. We consider possible reasons why proteasome inhibition may not be as effective in lung cancer and ways in which the efficacy might be improved in the future.

並列關鍵字

TRAIL ； Proteasome inhibitor ； Acquired resistance ； Multicellular resistance ； Three-dimensional Spheroid