Nano-hole induction by nanodiamond and nanoplatinum liquid, DPV576, reverses multidrug resistance in human myeloid leukemia (HL60/AR).

Recently nanoparticles have been extensively studied and have proven to be a promising candidate for cancer treatment and diagnosis. In the current study, we examined the chemo-sensitizing activity of a mixture of nanodiamond (ND) and nanoplatinum (NP) solution known as DPV576, against multidrug-resistant (MDR) human myeloid leukemia (HL60/AR) and MDR-sensitive cells (HL60). Cancer cells were cultured with different concentrations of daunorubicin (DNR) (1 × 10 (-9)-1 × 10 (-6) M) in the presence of selected concentrations of DPV576 (2.5%-10% v/v). Cancer cell survival was determined by MTT assay, drug accumulation by flow cytometry and confocal laser scanning microscopy (CLSM), and holes and structural changes by atomic force microscopy (AFM). Co-treatment of HL60/AR cells with DNR plus DPV576 resulted in the reduction of the IC50 to 1/4th. This was associated with increased incidences of holes inside the cells as compared with control untreated cells. On the other hand, HL60 cells did not show changes in their drug accumulation post-treatment with DPV576 and DNR. We conclude that DPV576 is an effective chemo-sensitizer as indicated by the reversal of HL60/AR cells to DNR and may represent a potential novel adjuvant for the treatment of chemo-resistant human myeloid leukemia

Peguero Electrocardiographic Left Ventricular Hypertrophy Criteria and Risk of Mortality

Background: Peguero electrocardiographic left ventricular hypertrophy (ECG-LVH) criteria are newly developed criteria that have shown better diagnostic performance than the traditional Cornell-voltage and Sokolow-Lyon criteria. However, prediction of poor outcomes rather than detection of increased left ventricular mass is becoming the primary use for ECG-LVH criteria which requires investigating any new ECG-LVH criteria in terms of prediction.Aims: To examine the prognostic significance of the newly developed Peguero ECG-LVH criteria.Methods: We compared the prognostic significance of Peguero ECG-LVH with Cornell-voltage and Sokolow-Lyon ECG-LVH criteria in 7,825 participants (age 59.8 ± 13.4 years; 52.7% women) from the third National Health and Nutrition Examination Survey who were free of major intraventricular conduction defects. ECG-LVH criteria were derived from digital ECG tracings processed at a central core laboratory.Results: At baseline, ECG-LVH was detected in 11.8% by Peguero; in 4.3% by Cornell voltage and in 6.4% by Sokolow-Lyon. During a median follow up of 13.8 years, 2,796 all-cause mortality events occurred. In multivariable models adjusted for demographics and cardiovascular risk factors, presence of Peguero ECG-LVH was associated with increased risk of all-cause mortality [HR (95% CI): 1.29 (1.16, 1.44)]. This association was not significantly different from the associations of Cornell voltage-LVH or Sokolow-Lyon LVH with all-cause mortality [HR (95%CI): 1.32 (1.12, 1.55) and 1.24 (1.07, 1.43), respectively; p-values for comparisons of these HRs with the HR of Peguero ECG-LVH 0.817 and 0.667, respectively]. Similar patterns of associations were observed with cardiovascular, ischemic heart disease and heart failure mortalities.Conclusion: Peguero ECG-LVH is predictive of increased risk of death similar to the traditional ECG-LVH criteria

PI3K-AKT-mTOR and NFκB Pathways in Ovarian Cancer: Implications for Targeted Therapeutics

Ovarian cancer is the most lethal gynecologic malignancy in the United States, with an estimated 22,530 new cases and 13,980 deaths in 2019. Recent studies have indicated that the phosphoinositol 3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), as well as the nuclear factor-κ light chain enhancer of activated B cells (NFκB) pathways are highly mutated and/or hyper-activated in a majority of ovarian cancer patients, and are associated with advanced grade and stage disease and poor prognosis. In this review, we will investigate PI3K/AKT/mTOR and their interconnection with NFκB pathway in ovarian cancer cells

Nano-hole induction by nanodiamond and nanoplatinum liquid, DPV576, reverses multidrug resistance in human myeloid leukemia (HL60/AR).

Recently nanoparticles have been extensively studied and have proven to be a promising candidate for cancer treatment and diagnosis. In the current study, we examined the chemo-sensitizing activity of a mixture of nanodiamond (ND) and nanoplatinum (NP) solution known as DPV576, against multidrug-resistant (MDR) human myeloid leukemia (HL60/AR) and MDR-sensitive cells (HL60). Cancer cells were cultured with different concentrations of daunorubicin (DNR) (1 × 10 (-9)-1 × 10 (-6) M) in the presence of selected concentrations of DPV576 (2.5%-10% v/v). Cancer cell survival was determined by MTT assay, drug accumulation by flow cytometry and confocal laser scanning microscopy (CLSM), and holes and structural changes by atomic force microscopy (AFM). Co-treatment of HL60/AR cells with DNR plus DPV576 resulted in the reduction of the IC50 to 1/4th. This was associated with increased incidences of holes inside the cells as compared with control untreated cells. On the other hand, HL60 cells did not show changes in their drug accumulation post-treatment with DPV576 and DNR. We conclude that DPV576 is an effective chemo-sensitizer as indicated by the reversal of HL60/AR cells to DNR and may represent a potential novel adjuvant for the treatment of chemo-resistant human myeloid leukemia

Metabolic Plasticity in Ovarian Cancer Stem Cells

Ovarian Cancer is the fifth most common cancer in females and remains the most lethal gynecological malignancy as most patients are diagnosed at late stages of the disease. Despite initial responses to therapy, recurrence of chemo-resistant disease is common. The presence of residual cancer stem cells (CSCs) with the unique ability to adapt to several metabolic and signaling pathways represents a major challenge in developing novel targeted therapies. The objective of this study is to investigate the transcripts of putative ovarian cancer stem cell (OCSC) markers in correlation with transcripts of receptors, transporters, and enzymes of the energy generating metabolic pathways involved in high grade serous ovarian cancer (HGSOC). We conducted correlative analysis in data downloaded from The Cancer Genome Atlas (TCGA), studies of experimental OCSCs and their parental lines from Gene Expression Omnibus (GEO), and Cancer Cell Line Encyclopedia (CCLE). We found positive correlations between the transcripts of OCSC markers, specifically CD44, and glycolytic markers. TCGA datasets revealed that NOTCH1, CD133, CD44, CD24, and ALDH1A1, positively and significantly correlated with tricarboxylic acid cycle (TCA) enzymes. OVCAR3-OCSCs (cancer stem cells derived from a well-established epithelial ovarian cancer cell line) exhibited enrichment of the electron transport chain (ETC) mainly in complexes I, III, IV, and V, further supporting reliance on the oxidative phosphorylation (OXPHOS) phenotype. OVCAR3-OCSCs also exhibited significant increase in CD36, ACACA, SCD, and CPT1A, with CD44, CD133, and ALDH1A1 exhibiting positive correlations with lipid metabolic enzymes. TCGA data show positive correlations between OCSC markers and glutamine metabolism enzymes, whereas in OCSC experimental models of GSE64999, GSE28799, and CCLE, the number of positive and negative correlations observed was significantly lower and was different between model systems. Appropriate integration and validation of data model systems with those in patients’ specimens is needed not only to bridge our knowledge gap of metabolic programing of OCSCs, but also in designing novel strategies to target the metabolic plasticity of dormant, resistant, and CSCs

Compound C Inhibits Ovarian Cancer Progression via PI3K-AKT-mTOR-NFκB Pathway

Epithelial Ovarian cancer (OvCa) is the leading cause of death from gynecologic malignancies in the United States, with most patients diagnosed at late stages. High-grade serous cancer (HGSC) is the most common and lethal subtype. Despite aggressive surgical debulking and chemotherapy, recurrence of chemo-resistant disease occurs in ~80% of patients. Thus, developing therapeutics that not only targets OvCa cell survival, but also target their interactions within their unique peritoneal tumor microenvironment (TME) is warranted. Herein, we report therapeutic efficacy of compound C (also known as dorsomorphin) with a novel mechanism of action in OvCa. We found that CC not only inhibited OvCa growth and invasiveness, but also blunted their reciprocal crosstalk with macrophages, and mesothelial cells. Mechanistic studies indicated that compound C exerts its effects on OvCa cells through inhibition of PI3K-AKT-NFκB pathways, whereas in macrophages and mesothelial cells, CC inhibited cancer-cell-induced canonical NFκB activation. We further validated the specificity of the PI3K-AKT-NFκB as targets of compound C by overexpression of constitutively active subunits as well as computational modeling. In addition, real-time monitoring of OvCa cellular bioenergetics revealed that compound C inhibits ATP production, mitochondrial respiration, and non-mitochondrial oxygen consumption. Importantly, compound C significantly decreased tumor burden of OvCa xenografts in nude mice and increased their sensitivity to cisplatin-treatment. Moreover, compound C re-sensitized patient-derived resistant cells to cisplatin. Together, our findings highlight compound C as a potent multi-faceted therapeutic in OvCa

SPARC Inhibits Metabolic Plasticity in Ovarian Cancer

The tropism of ovarian cancer (OvCa) to the peritoneal cavity is implicated in widespread dissemination, suboptimal surgery, and poor prognosis. This tropism is influenced by stromal factors that are not only critical for the oncogenic and metastatic cascades, but also in the modulation of cancer cell metabolic plasticity to fulfill their high energy demands. In this respect, we investigated the role of Secreted Protein Acidic and Rich in Cysteine (SPARC) in metabolic plasticity of OvCa. We used a syngeneic model of OvCa in Sparc-deficient and proficient mice to gain comprehensive insight into the paracrine effect of stromal-SPARC in metabolic programming of OvCa in the peritoneal milieu. Metabolomic and transcriptomic profiling of micro-dissected syngeneic peritoneal tumors revealed that the absence of stromal-Sparc led to significant upregulation of the enzymes involved in glycolysis, TCA cycle, and mitochondrial electron transport chain (ETC), and their metabolic intermediates. Absence of stromal-Sparc increased reactive oxygen species and perturbed redox homeostasis. Recombinant SPARC exerted a dose-dependent inhibitory effect on glycolysis, mitochondrial respiration, ATP production and ROS generation. Comparative analysis with human tumors revealed that SPARC-regulated ETC-signature inversely correlated with SPARC transcripts. Targeting mitochondrial ETC by phenformin treatment of tumor-bearing Sparc-deficient and proficient mice mitigated the effect of SPARC-deficiency and significantly reduced tumor burden, ROS, and oxidative tissue damage in syngeneic tumors. In summary, our findings provide novel insights into the role of SPARC in regulating metabolic plasticity and bioenergetics in OvCa, and shines light on its potential therapeutic efficacy