Pedersen Peter L
Department of Biological Chemistry, Johns Hopkins University, School of Medicine, 725 North Wolfe Street, Baltimore, MD, 21205-2185, USA,
J Bioenerg Biomembr. 2007 Jun;39(3):211-22. doi: 10.1007/s10863-007-9094-x.
As a new faculty member at The Johns Hopkins University, School of Medicine, the author began research on cancer in 1969 because this frequently fatal disease touched many whom he knew. He was intrigued with its viscous nature, the failure of all who studied it to find a cure, and also fascinated by the pioneering work of Otto Warburg, a biochemical legend and Nobel laureate. Warburg who died 1 year later in 1970 had shown in the 1920s that the most striking biochemical phenotype of cancers is their aberrant energy metabolism. Unlike normal tissues that derive most of their energy (ATP) by metabolizing the sugar glucose to carbon dioxide and water, a process that involves oxygen-dependent organelles called "mitochondria", Warburg showed that cancers frequently rely less on mitochondria and obtain as much as 50% of their ATP by metabolizing glucose directly to lactic acid, even in the presence of oxygen. This frequent phenotype of cancers became known as the "Warburg effect", and the author of this review strongly believed its understanding would facilitate the discovery of a cure. Following in the final footsteps of Warburg and caught in the midst of an unpleasant anti-Warburg, anti-metabolic era, the author and his students/collaborators began quietly to identify the key molecular events involved in the "Warburg effect". Here, the author describes via a series of sequential discoveries touching five decades how despite some impairment in the respiratory capacity of malignant tumors, that hexokinase 2 (HK-2), its mitochondrial receptor (VDAC), and the gene that encodes HK-2 (HK-2 gene) play the most pivotal and direct roles in the "Warburg effect". They discovered also that like a "Trojan horse" the simple lactic acid analog 3-bromopyruvate selectively enters the cells of cancerous animal tumors that exhibit the "Warburg effect" and quickly dissipates their energy (ATP) production factories (i.e., glycolysis and mitochondria) resulting in tumor destruction without harm to the animals.
作为约翰霍普金斯大学医学院的一名新教员，作者于1969年开始研究癌症，因为这种常常致命的疾病影响了许多他认识的人。他对癌症黏稠的特性、所有研究它的人都未能找到治愈方法感到好奇，同时也被生物化学界的传奇人物、诺贝尔奖获得者奥托·瓦尔堡的开创性工作所吸引。瓦尔堡于1970年去世，他在20世纪20年代就已表明，癌症最显著的生物化学表型是其异常的能量代谢。与正常组织通过将葡萄糖代谢为二氧化碳和水来获取大部分能量（ATP）的过程不同，这个过程涉及称为“线粒体”的依赖氧气的细胞器，瓦尔堡发现癌症常常较少依赖线粒体，即使在有氧气的情况下，也能通过将葡萄糖直接代谢为乳酸来获取高达50%的ATP。癌症的这种常见表型被称为“瓦尔堡效应”，本综述的作者坚信对其的理解将有助于找到治愈方法。追随瓦尔堡的最后脚步，并身处一个令人不快的反瓦尔堡、反代谢时代之中，作者及其学生/合作者开始悄然确定参与“瓦尔堡效应”的关键分子事件。在此，作者通过一系列跨越五十年的相继发现描述了，尽管恶性肿瘤的呼吸能力有所受损，但己糖激酶2（HK - 2）、其线粒体受体（VDAC）以及编码HK - 2的基因（HK - 2基因）在“瓦尔堡效应”中发挥着最关键和直接的作用。他们还发现，简单的乳酸类似物3 - 溴丙酮酸就像“特洛伊木马”一样，能选择性地进入表现出“瓦尔堡效应”的癌性动物肿瘤细胞，并迅速破坏其能量（ATP）生产工厂（即糖酵解和线粒体），从而导致肿瘤被破坏，且不会对动物造成伤害。
