The incidence of renal cell carcinoma (RCC) is increasing worldwide with an approximate 20% mortality rate. The challenge in RCC is the therapy-resistance. Cancer resistance to treatment employs multiple mechanisms due to cancer heterogeneity with multiple genetic and epigenetic alterations. These changes include aberrant overexpression of (1) anticancer cell death proteins (e.g., survivin/BIRC5), (2) DNA repair regulators (e.g., ERCC6) and (3) efflux pump proteins (e.g., ABCG2/BCRP); mutations and/or deregulation of key (4) oncogenes (e.g., MDM2, KRAS) and/or (5) tumor suppressor genes (e.g., TP5/p53); and (6) deregulation of redox-sensitive regulators (e.g., HIF, NRF2). Foci of tumor cells that have these genetic alterations and/or deregulation possess survival advantages and are selected for survival during treatment. We will review the significance of survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, TP5/p53, KRAS and AKT in treatment resistance as the potential therapeutic biomarkers and/or targets in RCC in parallel with our analized RCC-relevant TCGA genetic results from each of these gene/protein molecules. We then present our data to show the anticancer drug FL118 modulation of these protein targets and RCC cell/tumor growth. Finally, we include additional data to show a promising FL118 analogue (FL496) for treating the specialized type 2 papillary RCC.
Autoimmune (AI) diseases can affect many organs; however, the prostate has not been considered to be a primary target of these systemic inflammatory processes. Here, we utilize medical record data, patient samples, and in vivo models to evaluate the impact of inflammation, as seen in AI diseases, on prostate tissue. Human and mouse tissues are used to examine whether systemic targeting of inflammation limits prostatic inflammation and hyperplasia. Evaluation of 112,152 medical records indicates that benign prostatic hyperplasia (BPH) prevalence is significantly higher among patients with AI diseases. Furthermore, treating these patients with tumor necrosis factor (TNF)-antagonists significantly decreases BPH incidence. Single-cell RNA-seq and in vitro assays suggest that macrophage-derived TNF stimulates BPH-derived fibroblast proliferation. TNF blockade significantly reduces epithelial hyperplasia, NFκB activation, and macrophage-mediated inflammation within prostate tissues. Together, these studies show that patients with AI diseases have a heightened susceptibility to BPH and that reducing inflammation with a therapeutic agent can suppress BPH.
Arsenic trioxide (ATO), an FDA-approved drug for acute promyelocytic leukemia, also has great potential for treatment of solid tumors. Drug delivery powered by recent advances in nanotechnology has boosted the efficacy of many drugs, which is enlightening for applications of ATO in treating solid tumors. Herein, we reported arsenite-loaded multifunctional nanoparticles that are capable of pH-responsive ATO release for treating hepatocellular carcinoma (HCC) and real-time monitoring via magnetic resonance imaging. We fabricated these nanoparticles (designated as magnetic large-pore mesoporous silica nanoparticle (M-LPMSN)-NiAsOx) by loading nanoparticulate ATO prodrugs (NiAsOx) into the pores of large-pore mesoporous silica nanoparticles (LPMSNs) that contain magnetic iron oxide nanoparticles in the center. The surface of these nanodrugs was modified with a targeting ligand folic acid (FA) to further enhance the drug efficacy. Releasing profiles manifest the responsive discharging of arsenite in acidic environment. In vitro experiments with SMMC-7721 cells reveal that M-LPMSN-NiAsOx-FA nanodrugs have significantly higher cytotoxicity than traditional free ATO and induce more cell apoptosis. In vivo experiments with mice bearing H22 tumors further confirm the superior antitumor efficacy of M-LPMSN-NiAsOx-FA over traditional free ATO and demonstrate the outstanding imaging ability of M-LPMSN-NiAsOx-FA for real-time tumor monitoring. These targeted arsenite-loaded magnetic mesoporous silica nanoparticles integrating imaging and therapy hold great promise for treatment of HCC, indicating the auspicious potential of LPMSN-based nanoplatforms.
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