Druggable Biomarkers Altered in Clear Cell Renal Cell Carcinoma: Strategy for the Development of Mechanism-Based Combination Therapy.

Targeted therapeutics made significant advances in the treatment of patients with advanced clear cell renal cell carcinoma (ccRCC). Resistance and serious adverse events associated with standard therapy of patients with advanced ccRCC highlight the need to identify alternative 'druggable' targets to those currently under clinical development. Although the Von Hippel-Lindau (VHL) and Polybromo1 (PBRM1) tumor-suppressor genes are the two most frequently mutated genes and represent the hallmark of the ccRCC phenotype, stable expression of hypoxia-inducible factor-1α/2α (HIFs), microRNAs-210 and -155 (miR), transforming growth factor-beta (TGF-ß), nuclear factor erythroid 2-related factor 2 (Nrf2), and thymidine phosphorylase (TP) are targets overexpressed in the majority of ccRCC tumors.

MicroRNA Expression in Clear Cell Renal Cell Carcinoma Cell Lines and Tumor Biopsies: Potential Therapeutic Targets.

This study was carried out to quantitate the expression levels of microRNA-17, -19a, -34a, -155, and -210 (miRs) expressed in nine clear cell renal cell carcinoma (ccRCC) and one chromophobe renal cell carcinoma cell line with and without sarcomatoid differentiation, and in six primary kidney tumors with matching normal kidney tissues. The data in the five non-sarcomatoid ccRCC cell lines-RC2, CAKI-1, 786-0, RCC4, and RCC4/VHL-and in the four ccRCC with sarcomatoid differentiation-RCJ41T1, RCJ41T2, RCJ41M, and UOK-127-indicated that miR-17 and -19a were expressed at lower levels relative to miR-34a, -155, and -210. Compared with RPTEC normal epithelial cells, miR-34a, miR-155, and miR-210 were expressed at higher levels, independent of the sarcomatoid differentiation status and hypoxia-inducible factors 1α and 2α (HIFs) isoform expression.

Potential Role of Selenium in the Treatment of Cancer and Viral Infections.

Selenium has been extensively evaluated clinically as a chemopreventive agent with variable results depending on the type and dose of selenium used. Selenium species are now being therapeutically evaluated as modulators of drug responses rather than as directly cytotoxic agents. In addition, recent data suggest an association between selenium base-line levels in blood and survival of patients with COVID-19.

Current Landscape and the Potential Role of Hypoxia-Inducible Factors and Selenium in Clear Cell Renal Cell Carcinoma Treatment.

In the last two decades, the discovery of various pathways involved in renal cell carcinoma (RCC) has led to the development of biologically-driven targeted therapies. Hypoxia-inducible factors (HIFs), angiogenic growth factors, von Hippel⁻Lindau () gene mutations, and oncogenic microRNAs (miRNAs) play essential roles in the pathogenesis and drug resistance of clear cell renal cell carcinoma. These insights have led to the development of vascular endothelial growth factor (VEGF) inhibitors, Mechanistic target of rapamycin (mTOR) inhibitors, and immunotherapeutic agents, which have significantly improved the outcomes of patients with advanced RCC.

Non-Coding Micro RNAs and Hypoxia-Inducible Factors Are Selenium Targets for Development of a Mechanism-Based Combination Strategy in Clear-Cell Renal Cell Carcinoma-Bench-to-Bedside Therapy.

Durable response, inherent or acquired resistance, and dose-limiting toxicities continue to represent major barriers in the treatment of patients with advanced clear-cell renal cell carcinoma (ccRCC). The majority of ccRCC tumors are characterized by the loss of Von Hippel⁻Lindau tumor suppressor gene function, a stable expression of hypoxia-inducible factors 1α and 2α (HIFs), an altered expression of tumor-specific oncogenic microRNAs (miRNAs), a clear cytoplasm with dense lipid content, and overexpression of thymidine phosphorylase. The aim of this manuscript was to confirm that the downregulation of specific drug-resistant biomarkers deregulated in tumor cells by a defined dose and schedule of methylselenocysteine (MSC) or seleno-l-methionine (SLM) sensitizes tumor cells to mechanism-based drug combination.

Selenium targets resistance biomarkers enhancing efficacy while reducing toxicity of anti-cancer drugs: preclinical and clinical development.

Selenium (Se)-containing molecules exert antioxidant properties and modulate targets associated with tumor growth, metastasis, angiogenesis, and drug resistance. Prevention clinical trials with low-dose supplementation of different types of Se molecules have yielded conflicting results. Utilizing several xenograft models, we earlier reported that the enhanced antitumor activity of various chemotherapeutic agents by selenomethione and Se-methylselenocysteine in several human tumor xenografts is highly dose- and schedule-dependent.

Randomized phase II trial of selenomethionine as a modulator of efficacy and toxicity of chemoradiation in squamous cell carcinoma of the head and neck.

Aim: To investigate whether selenomethionine (SLM) reduces mucositis incidence in patients with head and neck squamous cell cancer (HNSCC) undergoing concurrent chemoradiation (CRT).

Methods: In this multi-institutional, randomized, double-blind phase II trial, patients with Stage III or IV HNSCC received SLM 3600 μg/m(2) or placebo twice daily for 7 d prior to CRT, once daily during CRT, and daily for 3 wk following CRT. CRT consisted of 70 Gy at 2 Gy per fraction with cisplatin 100 mg/m(2) IV on days 1, 22, and 43.

Effects of selenomethionine on acute toxicities from concurrent chemoradiation for inoperable stage III non-small cell lung cancer.

Aim: To prospectively determine the safety and tolerability of oral L-selenomethionine (SLM) with concurrent chemoradiation (CCRT) for Stage III non-small cell lung cancer (NSCLC) and estimate if the incidence and/or severity of adverse events could be reduced by its use.

Methods: Sixteen patients with stage III NSCLC were accrued to this single arm, phase II study. CCRT consisted of radiation given at 2 Gy per fraction for 30-33 fractions, 5 d per week with concurrent weekly IV paclitaxel 50 mg/m(2) followed by carboplatin dosed at an area under the time-concentration curve of 2.

Investigation of hydrophobically derivatized hyperbranched polyglycerol with PEGylated shell as a nanocarrier for systemic delivery of chemotherapeutics.

Unlabelled: We report the synthesis and characterization of a polymeric nanoparticle (NP) based on hyperbranched polyglycerol (HPG) containing a hydrophobic core and a hydrophilic shell, and assessed its suitability to be developed as a systemic anticancer drug carrier. HPG NP displayed low toxicity to primary cell cultures and were well-tolerated in mice after intravenous administration. When tested in mice tumor xenograft models, HPG NP accumulated significantly in the tumors with low accumulation in the liver and the spleen.

Constitutive expression of HIF-α plays a major role in generation of clear-cell phenotype in human primary and metastatic renal carcinoma.

The extensive lipid accumulation occurring in clear-cell renal cell carcinoma (ccRCC) results in a clear-cell cytoplasm. Hypoxia-inducible factor α (HIF-α) is constitutively expressed in many ccRCC and transcriptionally regulates >100 genes. In a recent breakthrough study, HIF-1α induced ccRCC in transgenic mice.

Se-methylselenocysteine offers selective protection against toxicity and potentiates the antitumour activity of anticancer drugs in preclinical animal models.

Background: Identification and development of drugs that can effectively modulate the therapeutic efficacy and toxicity of chemotherapy remain an unmet challenge. We evaluated the effects of Se-methylselenocysteine (MSC) on the toxicity and antitumour activity of cyclophosphamide, cisplatin, oxaliplatin, and irinotecan in animal models.

Methods: Cyclophosphamide, cisplatin, and oxaliplatin were administered by a single i.

MicroRNA-627 mediates the epigenetic mechanisms of vitamin D to suppress proliferation of human colorectal cancer cells and growth of xenograft tumors in mice.

Background & Aims: Vitamin D protects against colorectal cancer through unclear mechanisms. We investigated the effects of calcitriol (1α,25-dihydroxyvitamin D3; the active form of vitamin D) on levels of different microRNAs (miRNAs) in colorectal cancer cells from humans and xenograft tumors in mice.

Methods: Expression of miRNAs in colorectal cancer cell lines was examined using the Ambion mirVana miRNA Bioarray.

A novel small molecule FL118 that selectively inhibits survivin, Mcl-1, XIAP and cIAP2 in a p53-independent manner, shows superior antitumor activity.

Drug/radiation resistance to treatment and tumor relapse are major obstacles in identifying a cure for cancer. Development of novel agents that address these challenges would therefore be of the upmost importance in the fight against cancer. In this regard, studies show that the antiapoptotic protein survivin is a central molecule involved in both hurdles.

In vivo toxicity evaluation of gold-dendrimer composite nanodevices with different surface charges.

Composite nanodevices (CNDs) are multifunctional nanomaterials with potential uses in cancer imaging and therapy. Poly(amidoamine) dendrimer-based composite nanodevices are important members of this group and consist of an organic dendrimer component and an incorporated inorganic component, in this case, gold. This study addresses the short- (14 days) and long-term (78 days) in vivo toxicity of generation-5 (G5; 5 nm) PAMAM dendrimer-based gold-CNDs (Au-CNDs) with varying surface charges (positive, negative and neutral) in C57BL/6J male mice.

Selenium is a modulator of circadian clock that protects mice from the toxicity of a chemotherapeutic drug via upregulation of the core clock protein, BMAL1.

Selenium compounds are known as cancer preventive agents and are also able to ameliorate the toxicity associated with anti-cancer radiation and chemotherapy in mouse models. Sensitivity to the toxicity of chemotherapy is also modulated by the circadian clock, molecular time-keeping system that underlie daily fluctuations in multiple physiological and biochemical processes. Here we show that these two mechanisms are interconnected.

Ugt1a is required for the protective effect of selenium against irinotecan-induced toxicity.

Purpose: Irinotecan (CPT-11) is widely used for the treatment of patients with colorectal cancer. However, the adverse effects associated with the treatment have hindered the efficacies of irinotecan. We have shown that organic selenium compounds could significantly attenuate irinotecan-associated toxicity and enhance antitumor activity in xenograft tumor models.

Augmented therapeutic efficacy of irinotecan is associated with enhanced drug accumulation.

The goal of this study is to determine whether treatment with methylselenocysteine (MSC) results in differential uptake of irinotecan and its active metabolite (SN-38) between tumors of head and neck squamous cell carcinomas and normal tissue. The in vivo synergy between MSC and irinotecan is influenced by treatment schedule and associated with enhancement of tumor vessel maturation, intra-tumor concentration of SN-38 and apoptotic death of tumor cells. Normal tissue drug concentrations were not impacted by selenium treatment.

Bevacizumab enhances the therapeutic efficacy of Irinotecan against human head and neck squamous cell carcinoma xenografts.

Combining antiangiogenic agents with traditional cytotoxic chemotherapy offers the potential to target both vascular and cellular components of a growing tumor mass. Here, we examined the antitumor activity of the vascular endothelial growth factor antibody, Bevacizumab (Avastin®) in combination with the topoisomerase I inhibitor, Irinotecan (CPT-11) against human head and neck squamous cell carcinoma (HNSCC) xenografts. Bevacizumab was administered daily (at 5 or 20mg/kg) to nude mice bearing FaDu HNSCC xenografts for 28days with the first dose beginning seven days prior to Irinotecan (100mg/kg, weekly × 4).

Magnetic resonance and fluorescence-protein imaging of the anti-angiogenic and anti-tumor efficacy of selenium in an orthotopic model of human colon cancer.

Tumor progression and angiogenesis are intimately related. To understand the interrelationship between these two processes, real-time imaging can make a major contribution. In this report, fluorescent protein imaging (FPI) and magnetic resonance imaging (MRI) were utilized to demonstrate the effects of selenium on tumor progression and angiogenesis in an orthotopic model of human colon cancer.

Targeting the oncogenic protein beta-catenin to enhance chemotherapy outcome against solid human cancers.

Background: Beta-catenin is a multifunctional oncogenic protein that contributes fundamentally to cell development and biology. Elevation in expression and activity of β-catenin has been implicated in many cancers and associated with poor prognosis. Beta-catenin is degraded in the cytoplasm by glycogen synthase kinase 3 beta (GSK-3β) through phosphorylation.

Downregulation of cystine transporter xc by irinotecan in human head and neck cancer FaDu xenografts.

Background: The purpose of this study was: (1) to document the critical requirement of cystine for growth of human tumor cells in vitro, and (2) to determine the effect of the anticancer agent irinotecan on the cystine transporter x(c)(-) in head and neck FaDu xenografts.

Methods: Cell growth was measured by sulforhodamine B assay. xCT protein, glutathione (GSH) and DNA damage were determined using Western blot, spectrophotometry, and immunohistochemistry, respectively.

Architectural heterogeneity in tumors caused by differentiation alters intratumoral drug distribution and affects therapeutic synergy of antiangiogenic organoselenium compound.

Tumor differentiation enhances morphologic and microvascular heterogeneity fostering hypoxia that retards intratumoral drug delivery, distribution, and compromise therapeutic efficacy. In this study, the influence of tumor biologic heterogeneity on the interaction between cytotoxic chemotherapy and selenium was examined using a panel of human tumor xenografts representing cancers of the head and neck and lung along with tissue microarray analysis of human surgical samples. Tumor differentiation status, microvessel density, interstitial fluid pressure, vascular phenotype, and drug delivery were correlated with the degree of enhancement of chemotherapeutic efficacy by selenium.

Double immunohistochemical staining method for HIF-1alpha and its regulators PHD2 and PHD3 in formalin-fixed paraffin-embedded tissues.

Hypoxia-inducible factor (HIF-1alpha) is expressed in the nuclei of tumor cells under hypoxic conditions, and is regulated, in part, by cytoplasmic prolyl hydroxylases (PHDs). As HIF-1alpha is selectively expressed in tumor cells, inhibitors are being developed for cancer therapy. Although methods for the detection of HIF-1alpha and PHDs are available, an immunohistochemical double staining method for these markers in individual tumor cells is not available.