泛素-蛋白酶系統-腫瘤治療的新標靶

Ubiquitin Proteasome System -The New Target for Cancer Therapy

目前大部分癌症治療仍是以手術、放射治療和化學治療為主，但這些療法都有其不同的限制和副作用存在，近年來隨著生物科技與癌細胞分子生物學的快速發展，有許多抗癌的專一性標靶新藥，如針對各種癌細胞分泌的生長因子、細胞膜上的生長因子接受器或細胞內訊號傳導的阻斷劑，這幾年來在臨床醫學的應用是越來越多。例如可以對抗表皮細胞生長素接受器（epidermal growth factor receptor; EGFR）的Erbitux和Hercepin，對抗血管內皮細胞生長素（VEGF）的Avastin，抑制細胞內訊號傳遞酵素（tyrosine kinase）的Imatinib等標靶藥物，搭配放射或化學治療使用，在臨床上均有相當優異的療效，為罹癌患者提供更好的生活品質與更專一有效的治療方式。最近在抗癌新藥的研發上，相當值得注意的是蛋白酶體抑制劑（proteasome inhibitor; PI）藥物的發展。泛素（ubiquitin）是一種小分子酸性蛋白質，廣泛的分佈在不同的物種，從細菌到哺乳類動物體內都可發現它的存在。其主要功能是將細胞質老化、異常或過量的蛋白質加以標記，然後將被標記的蛋白質經由蛋白酶體（proteasome）予以分解代謝並再利用，以維持細胞內蛋白質的恆定。這是一種細胞內、耗能的化學反應，其反應必須消耗ATP才能進行，這種過程於細胞內會一再的循環以維持細胞的正常運作。而科學家利用蛋白酶體抑制劑干擾癌細胞的蛋白質恆定，確實可透過不同的分子機制，例如：p53, p21蛋白的累積、抑制蛋白質的轉譯、或影響NF-kB的活性等等，來達到抑癌的效果。對於這樣新穎且具前瞻性的治療方法，本文將對泛素－蛋白酶體系統、Bortezomib（目前研究最多的蛋白酶體抑制劑）與新一代的抑制劑相關的研究現況，以簡單的圖示與文字介紹，以期讓每位讀者在此新藥領域有更進一步的瞭解。

Currently, most cancer treatment is still based on surgery, radiation therapy and chemotherapy, but these therapies have their limitations and side effects exist. With the rapid development of biotechnology and cancer molecular biology in recent years, many anti-specific target for new drugs in cancer, such as for a variety of cancer cells secrete growth factors, growth factor receptor on the cellmembrane or intracellular signal transduction inhibitors for several years in the application of clinical medicine is more and more. The famous target drugs include Erbitux and Hercepin (against the epidermal growth factors receptor; EGFR), Avastin (against vascular endothelial growth factor; VEGF), and Imatinib (inhibition of intracellular signaling enzymes; tyrosine kinase), when with radiation or chemotherapy, have quite good efficacy in clinical practice to provide better quality of life and the more specific and effective treatment for cancer patients. Recently in the research and development of new anticancer drugs, quite worthy of note is the ubiquitin-proteasome system inhibitors drug development. Ubiquitin is a small molecule acidic protein, widely distributed in different species, from bacteria to mammals can be found of its existence. Its main function is to mark the unwanted, abnormal or excessive proteins in cytoplasm, and then the labeled protein degraded via the proteasome and re-use, in order to maintain constant intracellular protein. This is an energy consumption of the chemical reaction within a cell. The reaction must consume ATP to carry out, this repeated cycle process to make normal functioning of cells. The scientists used the ubiquitin-proteasome system inhibitors, interfere with cancer cell proteins constant, indeed through different molecular mechanisms, such as: p53 and p21 protein accumulation, inhibition of protein translation, or affect the activity of NF-kB to achieve the effect of tumor suppression. For the treatment of such innovative and forward-looking, this article will introduce the ubiquitin-proteasome system, Bortezomib and a new generation of inhibitors in a simple way, in order to let readers have a better understanding of this new drug.