Light-Responsive Polymeric Micellar Nanoparticles with Enhanced Formulation Stability.

Light-sensitive polymeric micelles have recently emerged as promising drug delivery systems for spatiotemporally controlled release of payload at target sites. Here, we developed diazonaphthoquinone (DNQ)-conjugated micellar nanoparticles that showed a change in polarity of the micellar core from hydrophobic to hydrophilic under UV light, releasing the encapsulated anti-cancer drug, doxetaxel (DTX). The micelles exhibited a low critical micelle concentration and high stability in the presence of bovine serum albumin (BSA) solution due to the hydrophobic and π-π stacking interactions in the micellar core. Cell studies showed enhanced cytotoxicity of DTX-loaded micellar nanoparticles upon irradiation. The enhanced stability would increase the circulation time of the micellar nanoparticles in blood, and enhance the therapeutic effectiveness for cancer therapy

Inhibition of lipid oxidation increases glucose metabolism and enhances 2-deoxy-2-[¹⁸F]fluoro-D-glucose uptake in prostate cancer mouse xenografts

Includes bibliographic references.PURPOSE: Prostate cancer (PCa) is the second most common cause of cancer-related death among men in the United States. Due to the lipid-driven metabolic phenotype of Pca, imaging with 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) is suboptimal, since tumors tend to have low avidity for glucose. PROCEDURES: We have used the fat oxidation inhibitor etomoxir (2-[6-(4-chlorophenoxy)-hexyl]oxirane-2-carboxylate) that targets carnitine-palmitoyl-transferase-1 (CPT-1) to increase glucose uptake in PCa cell lines. Small hairpin RNA specific for CPT1A was used to confirm the glycolytic switch induced by etomoxir in vitro. Systemic etomoxir treatment was used to enhance [¹⁸F]FDG-positron emission tomography ([¹⁸F]FDG-PET) imaging in PCa xenograft mouse models in 24 h. RESULTS: PCa cells significantly oxidize more of circulating fatty acids than benign cells via CPT-1 enzyme, and blocking this lipid oxidation resulted in activation of the Warburg effect and enhanced [¹⁸F]FDG signal in PCa mouse models. CONCLUSIONS: Inhibition of lipid oxidation plays a major role in elevating glucose metabolism of PCa cells, with potential for imaging enhancement that could also be extended to other cancers

Aberrant Lipid Metabolism Promotes Prostate Cancer: Role in Cell Survival under Hypoxia and Extracellular Vesicles Biogenesis

Prostate cancer (PCa) is the leading malignancy among men in United States. Recent studies have focused on the identification of novel metabolic characteristics of PCa, aimed at devising better preventive and therapeutic approaches. PCa cells have revealed unique metabolic features such as higher expression of several enzymes associated with de novo lipogenesis, fatty acid up-take and β-oxidation. This aberrant lipid metabolism has been reported to be important for PCa growth, hormone-refractory progression and treatment resistance. Furthermore, PCa cells effectively use lipid metabolism under adverse environmental conditions for their survival advantage. Specifically, hypoxic cancer cells accumulate higher amount of lipids through a combination of metabolic alterations including high glutamine and fatty acid uptake, as well as decreased fatty acid oxidation. These stored lipids serve to protect cancer cells from oxidative and endoplasmic reticulum stress, and play important roles in fueling cancer cell proliferation following re-oxygenation. Lastly, cellular lipids have also been implicated in extracellular vesicle biogenesis, which play a vital role in intercellular communication. Overall, the new understanding of lipid metabolism in recent years has offered several novel targets to better target and manage clinical PCa

Lipid Metabolism and Endocrine Resistance in Prostate Cancer, and New Opportunities for Therapy

Prostate cancer (PCa) is the most common cancer in men, and more than 10% of men will be diagnosed with PCa during their lifetime. Patients that are not cured with surgery or radiation are largely treated with endocrine therapies that target androgens or the androgen receptor (AR), a major driver of PCa. In response to androgen deprivation, most PCas progress to castrate resistant PCa, which is treated with anti-androgens like enzalutamide, but tumors still progress and become incurable. Thus, there is a critical need to identify cellular pathways that allow tumors to escape anti-androgen therapies. Epidemiological studies suggest that high-fat diets play important roles in PCa progression. Lipid metabolism rewires the PCa metabolome to support growth and resistance to endocrine therapies, although the exact mechanisms remain obscure. Therapeutic effects have been observed inhibiting several aspects of PCa lipid metabolism: Synthesis, uptake, and oxidation. Since AR remains a driver of PCa in advanced disease, strategies targeting both lipid metabolism and AR are starting to emerge, providing new opportunities to re-sensitize tumors to endocrine therapies with lipid metabolic approaches

Overcoming Resistance to Therapies Targeting the MAPK Pathway in BRAF-Mutated Tumours

Overactivation of the mitogen-activated protein kinase (MAPK) pathway is an important driver of many human cancers. First line, FDA-approved therapies targeting MAPK signalling, which include BRAF and MEK inhibitors, have variable success across cancers, and a significant number of patients quickly develop resistance. In recent years, a number of preclinical studies have reported alternative methods of overcoming resistance, which include promoting apoptosis, modulating autophagy, and targeting mitochondrial metabolism. This review summarizes mechanisms of resistance to approved MAPK-targeted therapies in BRAF-mutated cancers and discusses novel preclinical approaches to overcoming resistance

Light-Responsive Polymeric Micellar Nanoparticles with Enhanced Formulation Stability

Light-sensitive polymeric micelles have recently emerged as promising drug delivery systems for spatiotemporally controlled release of payload at target sites. Here, we developed diazonaphthoquinone (DNQ)-conjugated micellar nanoparticles that showed a change in polarity of the micellar core from hydrophobic to hydrophilic under UV light, releasing the encapsulated anti-cancer drug, doxetaxel (DTX). The micelles exhibited a low critical micelle concentration and high stability in the presence of bovine serum albumin (BSA) solution due to the hydrophobic and π–π stacking interactions in the micellar core. Cell studies showed enhanced cytotoxicity of DTX-loaded micellar nanoparticles upon irradiation. The enhanced stability would increase the circulation time of the micellar nanoparticles in blood, and enhance the therapeutic effectiveness for cancer therapy

CPT1A Supports Castration-Resistant Prostate Cancer in Androgen-Deprived Conditions

Prostate cancer (PCa) is the most common cancer in men, and the global burden of the disease is rising. The majority of PCa deaths are due to metastasis that are highly resistant to current hormonal treatments; this state is called castration-resistant prostate cancer (CRPC). In this study, we focused on the role of the lipid catabolism enzyme CPT1A in supporting CRPC growth in an androgen-dependent manner. We found that androgen withdrawal promoted the growth of CPT1A over-expressing (OE) tumors while it decreased the growth of CPT1A under-expressing (KD) tumors, increasing their sensitivity to enzalutamide. Mechanistically, we found that CPT1A-OE cells burned more lipid and showed increased histone acetylation changes that were partially reversed with a p300 specific inhibitor. Conversely, CPT1A-KD cells showed less histone acetylation when grown in androgen-deprived conditions. Our results suggest that CPT1A supports CRPC by supplying acetyl groups for histone acetylation, promoting growth and antiandrogen resistance