Titanium-gold-based chemotherapeutics for prostate and kidney cancer

描述(申请人提供)：肾癌是最常见的癌症之一，前列腺癌是美国男性发病率和死亡率的主要原因。显然有必要增加这些癌症单独使用或与靶向药物联合使用的化疗选择的数量。金属药物是当前癌症治疗的重要工具。常用的铂类药物在肾癌和前列腺癌中都失败了。钛基药物具有很高的临床前活性，具有抗癌治疗的潜力，特别是对转移性肾癌、转移性乳腺癌和前列腺癌的治疗。然而，他们的行动模式仍不清楚。最近的研究表明，金配合物在体内外对顺铂耐药癌细胞株也表现出显著的抗肿瘤活性，其作用机制与顺铂本身不同。初步结果表明，含钛和金的化合物在体外对前列腺癌细胞株具有显著的抗肿瘤作用。这项建议的长期目标是开发用于治疗肾癌和前列腺癌的异金属钛-金抗癌化疗药物。我们的假设是，在同一分子中加入两种具有抗肿瘤特性的不同金属将 提高它们的活性是因为：a)不同金属与多种生物靶标的相互作用，以及b)改善了异金属化合物的化学物理性质。我们将用膦、亚胺基膦和亚胺基膦修饰的环戊二烯(CP)配体进一步配位金，合成新的钛有机金属化合物。新制备的钛和钛-金衍生物的抗肿瘤性能和作用机制将使用不同的人肾和前列腺癌细胞株进行评估。目的1.合成含膦和亚胺基膦配体的钛及钛-金化合物，并测定其稳定性、体内外抗肿瘤活性。目的2：验证钛-金化合物活性增强是由于它们与多个生物靶点相互作用的假说。我们将评估这些化合物与不同生物分子靶标的相互作用，包括蛋白激酶、DNA、运输和线粒体蛋白，以及细胞死亡途径。本研究将阐明具有应用前景的非铂类抗肿瘤异金属化合物的作用机制。从这些化合物的激酶抑制特性研究中获得的知识将指导未来设计更具选择性或靶向性的化疗药物用于治疗人类。我们将与拉莫斯教授(夏威夷大学癌症中心)合作。

DESCRIPTION (provided by applicant): Kidney cancer is among the most common cancers and prostate cancer is a major cause of morbidity and mortality in men in the US. There is a clear need to increase the number of chemotherapeutic options for these cancers to use alone or in combination with targeted agents. Metallo-drugs are important tools in current cancer therapy. Platinum-derived drugs, commonly used, have failed in renal and prostate cancers. Titanium-based drugs have high preclinical activity and hold potential for anticancer therapy, especially for metastatic renal, metastatic breast and prostate cancers. However, their mode of action remains unclear. Recent studies indicate that gold complexes also display considerable anti-tumor properties both in vitro and in vivo against cisplatin-resistant cancer cell lines with different mode of action than cisplatin itself. Preliminary results demonstrate that compounds containing both titanium and gold have significant anti-tumor properties in vitro against prostate cancer cell lines. The long-term goal of this proposal is to develop heterometallic titanium-gold anticancer chemotherapeutics for the treatment of renal and prostate cancers. Our hypothesis is that the incorporation of two different metals with anti-tumor properties in the same molecule will improve their activity due to: a) interaction of the different metals with multiple biological targts and b) improved chemicophysical properties of the heterometallic compound. We will synthesize new titanium organometallic compounds with phosphine-, and iminophosphorane-modified cyclopentadienyl (Cp) ligands able to further coordinate gold moieties. The anti-tumor properties and mechanism of action of the new titanium and titanium-gold derivatives prepared will be evaluated using different human kidney and prostate cancer cell lines. Aim 1. To synthesise and to determine the stability, in vitro and in vivo anti-tumor activity of titanium and titanium-gold compounds with phosphine- and iminophosphorane-containing ligands. Aim 2: To test the hypothesis that the improved activity of titanium-gold compounds is due to their interactions with multiple biological targets. We will evaluate the interaction of these compounds with different biomolecular targets, including protein kinases, DNA, transport and mitochondrial proteins, and cell death pathways. This research will elucidate the mode of action of promising non-platinum anti-cancer heterometallic derivatives. The knowledge gained from the studies of the kinase inhibitory properties of these compounds will guide the design of more selective or targeted chemotherapeutics for treating humans in the future. We will work in collaboration with Prof. Ramos (University of Hawaii Cancer Center).