Institute of Nano Science and Technology, Habitat Centre, Phase 10, Mohali, Punjab 160062, India.
Disease Biology Laboratory, Regional Centre for Biotechnology, National Capital Region Biotech Science Cluster, Faridabad, Haryana 121001, India.
ACS Biomater Sci Eng. 2020 May 11;6(5):3139-3153. doi: 10.1021/acsbiomaterials.9b01844. Epub 2020 Apr 24.
Epigenetically regulated therapeutic intervention of cancer is an emerging era of research in the development of a promising therapy. Epigenetic changes are intrinsically reversible and providing the driving force to drug resistance in colorectal cancer (CRC). The regulation of polycomb group (PcG) proteins, BMI1 and EZH2, and the associated CRC progression hold promises for a novel treatment regime. The present study enlightens targeted photodynamic therapy (PDT) with potential photosensitizer hypericin nanocomposite in the development of epigenetic-based CRC therapy. We have synthesized hypericin-loaded transferrin nanoformulations (HTfNPs) overcoming the compromised hydrophobicity and poor bioavailability of the placebo drug. Targeted PDT with hypericin nanocomposite-induced BMI1 degradation assisted CRC retardation. In the present study, transferrin nanoparticles were reported to control the premature release of hypericin and improve its availability with better targeting at the disease site. Targeted intracellular internalization to colon cancer cells having a differential expression of transferrin receptors, biodistribution, stability, and pharmacokinetics provide promising applications in the nanodelivery system. Indeed, anticancer efficiency, cell cycle arrest at the G0/G1 phase, and elevated reactive oxygen species (ROS) generation confirm the anticancer effect of nanoformulation. In the exploration of mechanism, nanotherapeutic intervention by activation of PP2A, Caspase3 and inhibition of BMI1, EZH2, 3Pk, NFκB was evident. An exciting outcome of this study uncovered the camouflaged role of PP2A in the regulation of BMI1. PP2A mediates the ubiquitination/degradation of BMI1, which is revealed by changes in the physical interaction of PP2A and BMI1. Our study confirms the anticancer effect of HTfNP-assisted PDT by inducing PP2A-mediated BMI1 ubiquitination/degradation demonstrating an epigenetic-driven nanotherapeutic approach in CRC treatment.
癌症的表观遗传调控治疗干预是一个新兴的研究领域，为开发有前途的治疗方法提供了动力。表观遗传变化本质上是可逆的，并为结直肠癌（CRC）的耐药性提供了驱动力。多梳组（PcG）蛋白、BMI1 和 EZH2 的调控以及相关的 CRC 进展为新型治疗方案提供了希望。本研究通过开发基于表观遗传的 CRC 治疗方法，用潜在的光敏剂金丝桃素纳米复合材料启示靶向光动力疗法（PDT）。我们已经合成了负载金丝桃素的转铁蛋白纳米制剂（HTfNPs），克服了安慰剂药物的疏水性差和生物利用度低的问题。用金丝桃素纳米复合材料诱导 BMI1 降解的靶向 PDT 辅助 CRC 减缓。在本研究中，转铁蛋白纳米粒被报道可以控制金丝桃素的过早释放，并通过更好地靶向疾病部位来提高其可用性。对具有转铁蛋白受体差异表达的结肠癌细胞的靶向细胞内内化、生物分布、稳定性和药代动力学为纳米递药系统提供了有前途的应用。事实上，纳米制剂的抗癌效率、细胞周期停滞在 G0/G1 期和活性氧（ROS）生成的增加证实了其抗癌作用。在机制探索中，通过激活 PP2A、Caspase3 和抑制 BMI1、EZH2、3Pk、NFκB，纳米治疗干预是明显的。本研究的一个令人兴奋的结果揭示了 PP2A 在调节 BMI1 中的伪装作用。PP2A 介导 BMI1 的泛素化/降解，这是通过 PP2A 和 BMI1 的物理相互作用的变化来揭示的。我们的研究通过诱导 PP2A 介导的 BMI1 泛素化/降解证实了 HTfNP 辅助 PDT 的抗癌作用，展示了一种在 CRC 治疗中的表观遗传驱动的纳米治疗方法。
