Roseblade Ariane, Luk Frederick, Ung Alison, Bebawy Mary
Discipline of Pharmacy, Graduate School of Health, The University of Technology Sydney, PO Box 123 Broadway, NSW 2007 Australia.
Curr Cancer Drug Targets. 2015;15(3):205-14. doi: 10.2174/1568009615666150225121508.
Microparticles (MPs) are released from most eukaryotic cells after the vesiculation of the plasma membrane and serve as vectors of long and short-range signaling. MPs derived from multidrug resistant (MDR) cancer cells carry molecular components of the donor cell such as nucleic acids and proteins, and can alter the activity of drug-sensitive recipient cells through the transfer of their cargo. Given the substantial role of MPs in the acquisition and dissemination of MDR, we propose that the inhibition of MP release provides a novel therapeutic approach. This study characterises the effect of a panel of molecules known to act on MP-biosynthetic pathways. We demonstrate a differential effect by these molecules on MP inhibition that appear dependent on the release of intracellular calcium stores following activation with the calcium ionophore A23187. Calpain inhibitor, PD-150606; a selective inhibitor of Rho-associated, coiled-coil containing protein kinase (ROCK), Y-27632; and the vitamin B5 derivative pantethine, inhibited MP release only upon prior activation with A23187. Calpain inhibitor II showed significant inhibition in the absence of cell activation, whereas the vitamin B5 derivatives cystamine dihydrochloride and cysteamine hydrochloride showed no effect on MP inhibition under either condition. In contrast the classical pharmacological inhibitor of MDR, the calcium channel blocker Verapamil, showed an increase in MP formation on resting cells. These results suggest a potential role for calcium in the mechanism of action for PD-150606, Y-27632 and pantethine. These molecules, together with calpain inhibitor II have shown promise as modulators of MP release and warrant consideration as potential candidates for the development of an alternative therapeutic strategy for the prevention of MP-mediated MDR in cancer.
微粒（MPs）是大多数真核细胞在质膜囊泡化后释放出来的，可作为长距离和短距离信号传导的载体。源自多药耐药（MDR）癌细胞的MPs携带供体细胞的分子成分，如核酸和蛋白质，并可通过其货物转移改变药物敏感受体细胞的活性。鉴于MPs在MDR的获得和传播中起重要作用，我们提出抑制MPs释放提供了一种新的治疗方法。本研究表征了一组已知作用于MP生物合成途径的分子的效果。我们证明这些分子对MP抑制有不同的作用，这似乎取决于用钙离子载体A23187激活后细胞内钙库的释放。钙蛋白酶抑制剂PD - 150606；一种Rho相关的含卷曲螺旋蛋白激酶（ROCK）的选择性抑制剂Y - 27632；以及维生素B5衍生物泛硫乙胺，仅在预先用A23187激活后才抑制MP释放。钙蛋白酶抑制剂II在无细胞激活的情况下显示出显著抑制作用，而维生素B5衍生物盐酸半胱胺和盐酸半胱氨酸在两种条件下对MP抑制均无作用。相比之下，MDR的经典药理抑制剂钙通道阻滞剂维拉帕米在静息细胞上显示出MP形成增加。这些结果表明钙在PD - 150606、Y - 27632和泛硫乙胺的作用机制中可能起作用。这些分子与钙蛋白酶抑制剂II一起已显示出作为MP释放调节剂的前景，值得考虑作为开发预防癌症中MP介导的MDR的替代治疗策略的潜在候选药物。
