Peglated-H1/pHGFK1 nanoparticles enhance anti-tumor effects of sorafenib by inhibition of drug-induced autophagy and stemness in renal cell carcinoma

Abstract

Background Tumor targeting small molecular inhibitors are the most popular treatments for many malignant diseases, including cancer. However, the lower clinical response and drug resistance still limit their clinical efficacies. HGFK1, the first kringle domain of hepatocyte growth factor, has been defined as a potent anti-angiogenic factor. Here, we aimed to develop and identify novel nanoparticles—PH1/pHGFK1 as potential therapeutic agents for the treatment of renal cell carcinoma (RCC). Methods We produced a novel cationic polymer—PH1 and investigated the anti-tumor activity of PH1/pHGFK1 nanoparticle alone and its combination therapy with sorafenib in RCC cell line xenografted mice model. Then, we figured out its molecular mechanisms in human RCC cell lines in vitro. Results We firstly demonstrated that intravenous injection of PH1/pHGFK1 nanoparticles significantly inhibited tumor growth and prolonged the survival time of tumor-bearing mice, as well as synergistically enhanced anti-tumor activities of sorafenib. Furthermore, we elucidated that recombinant HGFK1 improved sorafenib-induced cell apoptosis and arrested cell cycle. In addition, HGFK1 could also decrease sorafenib-induced autophagy and stemness via blockading NF-κB signaling pathway in RCC both in vitro and in vivo. Conclusions HGFK1 could inhibit tumor growth, synergistically enhance anti-tumor activities of sorafenib and reverse its drug resistance evolution in RCC. Our results provide rational basis for clinical application of sorafenib and HGFK1 combination therapy in RCC patients. Electronic supplementary material The online version of this article (10.1186/s13046-019-1348-z) contains supplementary material, which is available to authorized users.

Autophagy as a Vital Therapy Target for Renal Cell Carcinoma

“…Moreover, the inhibition of autophagy with CQ increased the risk of TEM-induced cell death ( Singla and Bhattacharyya, 2017 ). The Kringle 1 domain of human hepatocyte growth factor (HGFK1) was found to enhance the anti-tumor activities of sorafenib and reverse resistance to this drug in RCC via the inhibition of autophagy ( Gao et al, 2019 ). Recently, a phase I/II trial in patients with RCC showed that the autophagy inhibition achieved by hydroxychloroquine enhanced the anti-tumor effects of mTOR inhibitors ( Haas et al, 2019 ).…”

Crucial Roles of microRNA-Mediated Autophagy in Urologic Malignancies

“…MiR-30a has been recognized as a potent inhibitor of autophagy by directly targeting Beclin-1 83 . Meanwhile, autophagy activation induced by sorafenib was involved in chemo-resistance in RCC cells 84 . Zheng et al .…”

“…MiR-30a has been recognized as a potent inhibitor of autophagy by directly targeting Beclin-1 [83]. Meanwhile, autophagy activation induced by sorafenib was involved in chemo-resistance in RCC cells [84]. Zheng et al [85] demonstrated that miR-30a overexpression significantly inhibits autophagy activation and enhances sorafenib-induced cytotoxicity in RCC cells.…”

Autophagy and Extracellular Vesicles, Connected to rabGTPase Family, Support Aggressiveness in Cancer Stem Cells

“…Indeed, the Atg4A protein is shown to be responsible for inducing the epithelial-mesenchymal transition as well as stemness properties in various gastric cancer cell lines and in vivo using mice models. As previously mentioned, CSCs are key actors in therapeutic resistance, which is why numerous studies on different types of cancer have proven the beneficial effects of autophagy inhibition on therapy sensitization [50,[65][66][67][68][69][70][71][72]. It has notably been demonstrated in non-small cell lung carcinoma (NSCLC) [67].…”