Jeffrey Cheah School of Medicine and Health Sciences, Monash University Sunway Campus, Jalan Lagoon Selatan, Bandar Sunway, Selangor Darul Ehsan, Malaysia.
Cancer Cell Int. 2012 Jun 18;12(1):30. doi: 10.1186/1475-2867-12-30.
RNA interference (RNAi) is a powerful approach in functional genomics to selectively silence messenger mRNA (mRNA) expression and can be employed to rapidly develop potential novel drugs against a complex disease like cancer. However, naked siRNA being anionic is unable to cross the anionic cell membrane through passive diffusion and therefore, delivery of siRNA remains a major hurdle to overcome before the potential of siRNA technology can fully be exploited in cancer. pH-sensitive carbonate apatite has recently been developed as an efficient tool to deliver siRNA into the mammalian cells by virtue of its high affinity interaction with the siRNA and the desirable size distribution of the resulting siRNA-apatite complex for effective cellular endocytosis. Moreover, internalized siRNA was found to escape from the endosomes in a time-dependent manner and efficiently silence gene expression.
Here we show that carbonate apatite-mediated delivery of siRNA against PLC-gamma-2 (PLCG2) and calmodulin 1 (CALM1) genes has led to the sensitization of a human cervical cancer cell line to doxorubicin- and paclitaxel depending on the dosage of the individual drug whereas no such enhancement in cell death was observed with cisplatin irrespective of the dosage following intracellular delivery of the siRNAs.
Thus, PLCG2 and CALM1 genes are two potential targets for gene knockdown in doxorubicin and paclitaxel-based chemotherapy of cervical cancer.
RNA 干扰（RNAi）是功能基因组学中一种强大的方法，可选择性地沉默信使 mRNA（mRNA）表达，可用于快速开发针对癌症等复杂疾病的潜在新型药物。然而，由于裸露的 siRNA 带负电荷，无法通过被动扩散穿过带负电荷的细胞膜，因此，在充分利用 siRNA 技术的潜力之前，siRNA 的递送达仍然是一个需要克服的主要障碍癌症。最近，碳酸磷灰石已被开发为一种有效的工具，通过其与 siRNA 的高亲和力相互作用以及所得 siRNA-磷灰石复合物的理想粒径分布，将 siRNA 递送至哺乳动物细胞，从而有效地进行细胞内吞作用。此外，发现内化的 siRNA 能够以时间依赖性的方式从内涵体中逃逸，并有效地沉默基因表达。
在这里，我们展示了碳酸磷灰石介导的针对 PLC-γ-2（PLCG2）和钙调蛋白 1（CALM1）基因的 siRNA 递送至人宫颈癌细胞系，导致阿霉素和紫杉醇的敏感性取决于单个药物的剂量，而无论 siRNA 内细胞递送后的剂量如何，顺铂均未观察到这种细胞死亡增强。
因此，PLCG2 和 CALM1 基因是基于阿霉素和紫杉醇的宫颈癌化疗中基因敲低的两个潜在靶点。
