A Trojan Horse in Drug Development: Targeting of Thapsigargins Towards Prostate Cancer Cells
A Trojan Horse in Drug Development: Targeting of Thapsigargins Towards Prostate Cancer Cells
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DOI：
10.2174/1871520610909030276
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发表时间：
2009-03-01
影响因子：
2.8
通讯作者：
Isaacs, John T.
中科院分区：
文献类型：
--
作者：
Christensen, S. Brogger;Skytte, Dorthe Mondrup;Isaacs, John T.
可用的化学治疗剂利用癌细胞的快速增殖。因此，缓慢的生长使得雄激素难治性前列腺癌对可用的药物具有抗性。目前没有治疗方法，当癌症已经转移到前列腺外时（T4阶段）。杀死细胞的细胞毒素，无论细胞周期的阶段，将能够杀死缓慢增殖的前列腺癌细胞。然而，缺乏选择性，妨碍了它们作为全身性药物的使用。前列腺癌细胞分泌特征性蛋白水解酶，例如。G. PSA和hK 2，具有不寻常的底物特异性。细胞毒素与肽（其是PSA或hK 2的选择性底物）的缀合将提供前药，活性药物仅在癌细胞附近从其释放。基于这种策略，已经构建了靶向前列腺癌细胞的前体药物，并评估其作为前列腺癌的潜在药物。毒胡萝卜素作为凋亡剂的效力使得这些天然存在的倍半萜内酯成为有吸引力的先导化合物。对毒胡萝卜素的结构-活性关系和化学的深入研究已经使得能够构建能够与肽缀合的有效衍生物。对毒胡萝卜素作用机制的研究表明，其细胞毒性是基于其抑制细胞内肌质/内质网钙泵的能力。
Available chemotherapeutics take advantage of the fast proliferation of cancer cells. Consequently slow growth makes androgen refractory prostate cancer resistant towards available drugs. No treatment is available at the present, when the cancer has developed metastases outside the prostate (T4 stage). Cytotoxins killing cells irrespective of the phase of the cell cycle will be able to kill slowly proliferating prostate cancer cells. Lack of selectivity, however, prevents their use as systemic drugs. Prostate cancer cells secrete characteristic proteolytic enzymes, e. g. PSA and hK2, with unusual substrate specificity. Conjugation of cytotoxins with peptides, which are selective substrates for PSA or hK2, will afford prodrugs, from which the active drug only will be released in close vicinity of the cancer cells. Based on this strategy prodrugs targeted at prostate cancer cells have been constructed and evaluated as potential drugs for prostate cancer. The potency of the thapsigargins as apoptotic agents make these naturally occurring sesquiterpene lactones attractive lead compounds. Intensive studies on structure-activity relationships and chemistry of the thapsigargins have enabled construction of potent derivatives enabling conjugation with peptides. Studies on the mechanism of action of the thapsigargins have revealed that the cytoxicity is based on their ability to inhibit the intracellular sarco-/endoplasmtic calcium pump.