Therapeutic targeting of polo-like kinase 1 using RNA-interfering nanoparticles (iNOPs) for the treatment of non-small cell lung cancer

Abstract

Non-small cell lung cancer (NSCLC) remains the most common cause of cancer death worldwide due its resistance to chemotherapy and aggressive tumor growth. Polo-like kinase 1 (PLK1) is a serine-threonine protein kinase which is overexpressed in cancer cells, and plays a major role in regulating tumor growth. A number of PLK1 inhibitors are in clinical trial; however, poor tumor bioavailability and off-target effects limit their efficacy. Short-interfering-RNA (siRNA) holds promise as a class of therapeutics, which can selectively silence disease-causing genes. However, siRNA cannot enter cells without a delivery vehicle. Herein, we investigated whether RNAi-interfering nanoparticles could deliver siRNA to NSCLC cells and silence PLK1 expression in vitro and in vivo. iNOP-7 was non-toxic, and delivered siRNA with high efficiency to NSCLC cells. iNOP-7-PLK1 siRNA silenced PLK1 expression and reduced NSCLC growth in vitro. Notably, iNOP-7 delivered siRNA to orthotopic lung tumors in mice, and administration of iNOP-7-PLK1 siRNA reduced lung tumor burden. These novel data show that iNOP-7 can deliver siRNA against PLK1 to NSCLC cells, and decrease cell proliferation both in vitro and in vivo. iNOP-7-PLK1 siRNA may provide a novel therapeutic strategy for the treatment of NSCLC as well as other cancers which aberrantly express this gene.

Cross Talk between Wnt/β-Catenin and CIP2A/Plk1 Signaling in Prostate Cancer: Promising Therapeutic Implications

“…Moreover, Plk1 inhibition in androgen-insensitive PCa has been reported to induce necroptosis (73) and cause mitotic arrest and defects in both cytokinesis and centrosome formation of PCa cells (72). These findings are consistent with the data published in many other tumor types, in which tumor growth inhibition and enhanced apoptosis have been observed in preclinical studies using Plk-1 specific small interfering RNAs (74)(75)(76)(77)(78)(79)(80)(81)(82)(83)(84)(85)(86). Another interesting issue of therapeutic relevance is that Plk-1 inhibition has been reported to enhance both radiation and anticancer drug efficacy in many tumor types (87)(88)(89)(90)(91)(92).…”

PLK1, A Potential Target for Cancer Therapy

“…Oncogenes and tumor suppressor genes are mostly related to cell cycle regulation, and dysregulation of the cell cycle is the main cause of cancer [19]. Since PLK1 was found to be highly expressed in primary tumor tissues more than two decades ago [20], its role as an oncogene has been identified by many studies [21], [22]. A number of studies have revealed that PLK1 is overexpressed in cancers compared with normal controls in various types of human cancers such as glioma [23], thyroid carcinoma [24], head and neck squamous cell carcinoma [25], melanoma [26], colorectal cancers [27], esophageal carcinoma [28], ovarian carcinoma [29], breast cancer [30], and prostate cancer [31].…”

“…Spänkuch-Schmitt et al showed that siRNAs targeting PLK1 reduced cancer cell proliferation, whereas they had almost no effect on human mammary epithelial cells [110]. McCarroll et al targeted PLK1 by RNA-interfering nanoparticle-7 that reduced non–small cell lung cancer cell proliferation in a mouse model [22]. A number of studies have suggested that targeting PLK1 by siRNA could be a viable approach to cancer therapy [9], [60], [111].…”

Nanoparticles for siRNA-Based Gene Silencing in Tumor Therapy

“…Thus, RNAi has affected cancer therapy by downregulating tumorigenic genes, resulting in pro-apoptotic and anti-metastatic effects, while having negligible effects on healthy tissues. The specificity and therapeutic efficiency of RNAi can be increased with the help of nanoparticle carriers, as per many recent reports in both in vitro and in vivo cancer models [26], [27], [28], [29]. Though no major clinical breakthroughs have yet been achieved for RNAi, it is hoped that, with the help of advanced delivery strategies, RNAi might achieve the potential for clinical success in the not-too-distant future.…”