Brazilian Nuclear Energy Commission, Nuclear Engineering Institute, Rua Helio de Almeida 75, Ilha do Fundão, CEP 21941-614 Rio de Janeiro, Brazil.
Laboratory of Cellular and Molecular Hemato-Oncology, Program of Molecular Hemato-Oncology, Brazilian National Cancer Institute (INCA), CEP 20230130 Rio de Janeiro, Brazil.
Int J Mol Sci. 2020 Apr 10;21(7):2630. doi: 10.3390/ijms21072630.
The cancer multidrug resistance is involved in the failure of several treatments during cancer treatment. It is a phenomenon that has been receiving great attention in the last years due to the sheer amount of mechanisms discovered and involved in the process of resistance which hinders the effectiveness of many anti-cancer drugs. Among the mechanisms involved in the multidrug resistance, the participation of ATP-binding cassette (ABC) transporters is the main one. The ABC transporters are a group of plasma membrane and intracellular organelle proteins involved in the process of externalization of substrates from cells, which are expressed in cancer. They are involved in the clearance of intracellular metabolites as ions, hormones, lipids and other small molecules from the cell, affecting directly and indirectly drug absorption, distribution, metabolism and excretion. Other mechanisms responsible for resistance are the signaling pathways and the anti- and pro-apoptotic proteins involved in cell death by apoptosis. In this study we evaluated the influence of three nanosystem (Graphene Quantum Dots (GQDs), mesoporous silica (MSN) and poly-lactic nanoparticles (PLA)) in the main mechanism related to the cancer multidrug resistance such as the Multidrug Resistance Protein-1 and P-glycoprotein. We also evaluated this influence in a group of proteins involved in the apoptosis-related resistance including cIAP-1, XIAP, Bcl-2, BAK and Survivin proteins. Last, colonogenic and MTT (3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide) assays have also been performed. The results showed, regardless of the concentration used, GQDs, MSN and PLA were not cytotoxic to MDA-MB-231 cells and showed no impairment in the colony formation capacity. In addition, it has been observed that P-gp membrane expression was not significantly altered by any of the three nanomaterials. The results suggest that GQDs nanoparticles would be suitable for the delivery of other multidrug resistance protein 1 (MRP1) substrate drugs that bind to the transporter at the same binding pocket, while MSN can strongly inhibit doxorubicin efflux by MRP1. On the other hand, PLA showed moderate inhibition of doxorubicin efflux by MRP1 suggesting that this nanomaterial can also be useful to treat MDR (Multidrug resistance) due to MRP1 overexpression.
癌症多药耐药性涉及癌症治疗过程中几种治疗方法的失败。由于发现并涉及耐药过程的机制数量众多，这一现象在近年来受到了极大关注，该过程阻碍了许多抗癌药物的有效性。在涉及多药耐药性的机制中，ATP 结合盒（ABC）转运蛋白的参与是主要的。ABC 转运蛋白是一组参与将细胞内底物外排的质膜和细胞内细胞器蛋白，在癌症中表达。它们参与清除细胞内代谢物，如细胞内离子、激素、脂质和其他小分子，直接和间接地影响药物的吸收、分布、代谢和排泄。其他耐药机制包括信号通路和参与细胞凋亡的抗凋亡和促凋亡蛋白。在这项研究中，我们评估了三种纳米系统（石墨烯量子点（GQDs）、介孔硅（MSN）和聚乳酸纳米粒子（PLA））对与癌症多药耐药性相关的主要机制的影响，如多药耐药蛋白 1 和 P-糖蛋白。我们还评估了一组与凋亡相关耐药性相关的蛋白质的影响，包括 cIAP-1、XIAP、Bcl-2、BAK 和 Survivin 蛋白。最后，还进行了集落形成和 MTT（3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四唑溴盐）测定。结果表明，无论使用何种浓度，GQDs、MSN 和 PLA 对 MDA-MB-231 细胞均无细胞毒性，且不会损害集落形成能力。此外，观察到三种纳米材料均未显著改变 P-糖蛋白的膜表达。结果表明，GQDs 纳米粒子可适用于输送其他与多药耐药蛋白 1（MRP1）结合的药物，这些药物与转运蛋白在同一结合口袋结合，而 MSN 可通过 MRP1 强烈抑制阿霉素外排。另一方面，PLA 对 MRP1 介导的阿霉素外排显示出适度的抑制作用，这表明该纳米材料也可用于治疗由于 MRP1 过度表达而导致的多药耐药性。
