Novel Prostate cancer therapy based on m-aconitase inhibition

摘要 早期前列腺癌患者的治疗选择主要包括观察等待，根治性治疗， 乳腺癌切除术或放射治疗，而对于晚期疾病的患者， 化疗/放疗是优选的选择。然而，所有这些选择都有非常严重的一面 方面的影响.虽然早期癌症可以通过根治性直肠癌切除术来解决，但晚期癌症却不是这样。 处于激素难治性和/或转移性阶段的癌症。副作用更小， 需要有效性，特别是对于后一种情况。 我们提出的方法利用了前列腺的固有特性，即前列腺素的积累。 前列腺腺上皮细胞分泌大量柠檬酸盐和锌。锌作为一种抑制剂， m-乌头酸酶，这种酶控制柠檬酸进入克雷布斯循环的第一反应。三羧酸 这些细胞中的细胞周期被截短，合成的柠檬酸盐积累以分泌到前列腺液中。然而，在这方面， 在前列腺癌细胞中，由于锌转运蛋白的下调而丧失了积累锌的能力。这 缺乏导致间乌头酸酶活性正常化和柠檬酸盐通过功能性克雷布斯循环氧化 导致38个ATP/葡萄糖，相比之下， 正常前列腺细胞因此，恶性细胞变得能量高效，而不是能量低效， 专门的产生柠檬酸盐的前列腺上皮细胞，并将它们的表型改变为“柠檬酸盐氧化”。 在这项研究中，我们提出抑制间乌头酸酶，目的是逆转“柠檬酸氧化”表型， 前列腺癌这将通过使用前列腺特异性膜抗原将锌递送到体内肿瘤来完成 （PSMA）靶向的图像引导的脂质体，其负载有锌。我们预期锌对间乌头酸酶的抑制作用 导致癌细胞产生的能量急剧减少，最终导致能量匮乏 和细胞死亡。由于监测含锌脂质体的递送将为我们提供改变 在研究和调整治疗方案的过程中，拟定的脂质体将包含 用于磁共振和光学成像的成像报告物。我们建议合成和测试含锌 PSMA特异性图像引导脂质体首先在体外，然后在非转移性和非转移性肿瘤中进行体内初步研究。 前列腺癌的转移性小鼠模型。后一个阶段具有重要意义，因为它是高级阶段， 导致前列腺癌患者的高死亡率。

ABSTRACT Treatment options for patients with early-stage prostate cancer include mostly watchful waiting, radical prostatectomy or radiation therapy, whereas for patients with advanced disease hormone therapy followed by chemotherapy/radiotherapy are the preferred options. However, all of these options suffer from very serious side effects. While early-stage cancers can be addressed with radical prostatectomy, this is not the case for advanced cancers at hormone refractory and/or metastatic stages. Approaches with lesser side effects and more effectiveness are needed, especially for the latter scenarios. Our proposed approach takes advantage of the innate property of the prostate gland, which is accumulation of enormously high levels of citrate and zinc by the prostate glandular epithelial cells. Zinc serves as an inhibitor of m-aconitase, the enzyme, which controls the first reaction for the entry of citrate into the Krebs cycle. The Krebs cycle in these cells is truncated, and synthesized citrate accumulates for secretion into prostatic fluid. However, in prostate cancer cells the ability to accumulate zinc is lost due to downregulation of zinc transporter. This deficiency leads to normalization of m-aconitase activity and oxidation of citrate via a functional Krebs cycle resulting in 38 ATP/glucose compared to 14 ATP/glucose produced from the aerobic oxidation of glucose in normal prostate cells. Thus, the malignant cells become energy-efficient in contrast to the energy-inefficient, specialized citrate-producing prostate epithelial cell and change their phenotype to a “citrate-oxidizing”. In this study we propose to inhibit m-aconitase with the goal to reverse the “citrate-oxidizing” phenotype in prostate cancer. This will be done by delivering zinc to tumors in vivo using prostate specific membrane antigen (PSMA)-targeted image-guided liposomes loaded with zinc. We expect that inhibition of m-aconitase by zinc will cause a dramatic decrease in energy production by cancer cells, which will ultimately lead to energy deprivation and cell death. Since monitoring the delivery of Zn-containing liposomes will provide us with opportunity to alter formulation in the course of investigation and adjust treatment regimen, the proposed liposomes will contain imaging reporters for magnetic resonance and optical imaging. We propose to synthesize and test Zn-containing PSMA-specific image-guided liposomes first in vitro and then in pilot studies in vivo in non-metastatic and metastatic mouse models of prostate cancer. The latter is of high significance since it is the advanced stage that causes high mortality in prostate cancer patients.