Here, we investigated the mechanism of antiproliferative action in cancer cells of new compounds structurally derived from oxaliplatin, namely a pair of enantiomers [Pt(OXA)(1R,2R-DACHEX)] (1) and [Pt(OXA)(1S,2S-DACHEX)] (2) (OXA = oxalate, DACHEX = trans-1,2-diamino-4-cyclohexene). While oxaliplatin is used almost exclusively to treat colorectal and other gastrointestinal cancers, new complex 1 shows instead high potency in malignant pancreatic adenocarcinoma PSN1 cells including superior selectivity for pancreatic cancer over noncancerous cells. Utilizing a multi-platform biochemical approach to study the unique features of the mechanism of action of this new platinum-based drug, we show that 1 has a much greater ability to penetrate pancreatic tumors than its S,S enantiomer 2 and oxaliplatin, and to be transported into cells as bound to plasma proteins. Additionally, the mechanism of action of 1 and, to a lesser extent, oxaliplatin in pancreatic cancer cells involves alterations of the lipogenesis pathway, namely inhibition of de novo lipid synthesis, acting by a new mechanism not yet considered for anticancer action of clinically used antitumor platinum drugs. These data highlight the functional diversity of platinum anticancer compounds and the potential benefits of finding new anticancer drugs applying a mechanism-based rationale.

中文翻译：

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含有 trans-1,2-diamino-4-cyclohexene 配体的 1R,2R 对映体的 Pt(II) 复合物可有效选择性地抑制侵袭性胰腺癌细胞的活力并改变其脂质代谢

在这里，我们研究了结构上源自奥沙利铂的新化合物，即一对对映异构体 [Pt(OXA)(1 R ,2 R -DACHEX)] ( 1 ) 和 [Pt(OXA)( 1 S ,2 S -DACHEX)] ( 2 ) (OXA = 草酸盐，DACHEX =反式-1,2-二氨基-4-环己烯)。虽然奥沙利铂几乎专门用于治疗结直肠癌和其他胃肠道癌症，但新的复合物1相反，在恶性胰腺癌 PSN1 细胞中显示出高效力，包括对胰腺癌的选择性优于非癌细胞。利用多平台生化方法来研究这种新的铂类药物作用机制的独特特征，我们表明1比其S、S对映体2和奥沙利铂具有更强的穿透胰腺肿瘤的能力，并且与血浆蛋白结合后被转运到细胞中。此外，1和奥沙利铂在胰腺癌细胞中的作用机制涉及脂肪生成途径的改变，即从头抑制脂质合成，通过一种尚未被考虑用于临床使用的抗肿瘤铂类药物的抗癌作用的新机制起作用。这些数据突出了铂类抗癌化合物的功能多样性以及应用基于机制的原理寻找新抗癌药物的潜在好处。