Autophagy‐Induced Apoptosis in Lung Cancer Cells by a Novel Digitoxin Analog

Kulkarni, Yogesh; Kaushik, Vivek; Azad, Neelam; Wright, Clayton; Rojanasakul, Yon; O’Doherty, George A.; Iyer, Anand Krishnan V.

doi:10.1002/jcp.25129

Cited by 26 publications

(24 citation statements)

References 49 publications

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“…The degradation products of the autophagosomal cargo, which includes sugars, nucleosides or nucleotides, amino acids, and fatty acids, can be transported back to the cytoplasm, presumably to re-enter cellular metabolism. However, sustained autophagic flux may lead to excessive self-degradation of cellular components essential for survival (such as mitochondria), triggering cell death [56]. Regardless of mTOR activation, autophagy can be a consequence of endoplasmic reticulum (ER) stress induction in response to glucose deprivation and decreased ATP levels [47,57].…”

Section: Autophagy Inductionmentioning

confidence: 99%

2-Deoxy-d-Glucose and Its Analogs: From Diagnostic to Therapeutic Agents

Pająk

Siwiak

Sołtyka

et al. 2019

IJMS

343

267

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The ability of 2-deoxy-d-glucose (2-DG) to interfere with d-glucose metabolism demonstrates that nutrient and energy deprivation is an efficient tool to suppress cancer cell growth and survival. Acting as a d-glucose mimic, 2-DG inhibits glycolysis due to formation and intracellular accumulation of 2-deoxy-d-glucose-6-phosphate (2-DG6P), inhibiting the function of hexokinase and glucose-6-phosphate isomerase, and inducing cell death. In addition to glycolysis inhibition, other molecular processes are also affected by 2-DG. Attempts to improve 2-DG's drug-like properties, its role as a potential adjuvant for other chemotherapeutics, and novel 2-DG analogs as promising new anticancer agents are discussed in this review.using gluconeogenesis [5]. The hydrophilic nature of glucose requires specific glucose transporter proteins (GLUTs) to facilitate cellular uptake [6]. Higher glucose utilization by tumor cells requires overexpression of GLUT transporters to increase glucose uptake over 20-30 fold as compared to normal cells [7,8].Once inside the cell, glucose enters a cycle of changes to release energy in the form of ATP. Normal cells with access to oxygen utilize glycolysis to metabolize glucose into two molecules of pyruvate and form two molecules of ATP. The pyruvate is further oxidized in the mitochondria to acetyl-CoA via the pyruvate dehydrogenase complex. Acetyl-CoA then enters the Krebs cycle, in which it is oxidized into 2 molecules of CO 2 . The electrons derived from this process are used to create three molecules of NADH and one molecule of FADH 2 . These electron carrier molecules are reoxidized through the oxidoreductive systems of the respiratory chain, which drives ATP formation from ADP and inorganic phosphate (P i ) [9]. As a result of oxidative phosphorylation, 30 ATP molecules are generated from one molecule of glucose versus a net of 2 from glycolysis [9,10]. Oxygen is vitally important for this process as the final electron acceptor, allowing complete oxidation of glucose. In the case of insufficient oxygen concentrations, for example in skeletal muscle during periods of intense exertion, cells fall back on glycolysis, an ancient metabolic pathway evolved before the accumulation of significant atmospheric oxygen. Pyruvate, the end product of glycolysis, is reduced to lactate via lactic acid fermentation, cycling NADH back to NAD + [11]. The comparison of glucose metabolic pathways is presented in Figure 1.

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Section: Autophagy Inductionmentioning

confidence: 99%

2-Deoxy-d-Glucose and Its Analogs: From Diagnostic to Therapeutic Agents

Pająk

Siwiak

Sołtyka

et al. 2019

IJMS

343

267

View full text Add to dashboard Cite

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“…However, patients treated with both HCQ and gemcitabine who met criteria for HCQ response via peripheral blood mononuclear cell LC3 staining demonstrated marked improvement in disease-free and overall survival (Boone et al, 2015). Accordingly, there are several strategies underway to develop new and more potent autophagy inhibitors which may yield better clinical results (Kulkarni et al, 2016;Liu et al, 2011;McAfee et al, 2012;Wang et al, 2015;Zhao et al, 2015).…”

Section: Inhibitors Of Intermediary Metabolismmentioning

confidence: 99%

Employing Metabolism to Improve the Diagnosis and Treatment of Pancreatic Cancer

2017

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Pancreatic ductal adenocarcinoma is on pace to become the second leading cause of cancer-related death. The high mortality rate results from a lack of methods for early detection and the inability to successfully treat patients once diagnosed. Pancreatic cancer cells have extensively reprogrammed metabolism, which is driven by oncogene-mediated cell-autonomous pathways, the unique physiology of the tumor microenvironment, and interactions with non-cancer cells. In this review, we discuss how recent efforts delineating rewired metabolic networks in pancreatic cancer have revealed new in-roads to develop detection and treatment strategies for this dreadful disease.

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“…Recently autophagy has gained much attention as the potent alternative mechanism to fight cancer. Although the impact of autophagy on cancer cell death is a topic of intense debate 71,72 , one school of oncologists with their data supports the alternate mechanism of autophagy in the death of cancer cells [73][74][75] . There are emerging evidences that autophagy, a caspase-independent cell death process, plays critical roles in the generation of antineoplastic responses and mediates caspase-independent malignant cell death 76 .…”

Section: Discussionmentioning

confidence: 99%

Anti-cancer property of Lenzites betulina (L) Fr. on cervical cancer cell lines and its anti-tumor effect on HeLa-implanted mice

Sanyal

Ghosh

2019

Preprint

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In global scenario cervical cancer is increasing. New drugs from natural compounds are in search. Mushrooms are now recognized as miniature pharmaceutical factories producing hundreds of novel constituents. We have taken ethanolic extract Lenzities betulina (LBE) wild mushroom for evaluation of its as anti-cancer property against cervical cancer cell lines e.g. HeLa, CaSki and SiHa and anti tumor activity against HeLa implanted tumor on mice. The extraction was done by dip and stirring method in 90% ethanol for 72 h. For evaluation of anti-cervical cancer, several assays were performed such as MTT assay, cell morphology by phase contrast microscope and F-action polymerization by Laser scanning confocal microscope and nuclear morphology DAPI staining under inverted fluorescence microscope, MMP, ROS, cell cycle, autophagy and stem cell population by flow cytometry and DNA laddering were done. Western blotting was done for protein expression. To evaluate anti-metastatic activity, anti-cologenic assay and wound healing assay were adopted. For chemo-analysis of the LBE, GC-MS was done. The results from Cytotoxicity assay showed that at highest dose of LBE (1000 µg/ml) after 24 h, percentage of cell inhibitions were 85.13 %, 77.13 % and 47.70 % against HeLa , CaSki and SiHa respectively and the calculated IC 50 values were 492.52 ± 2.6 µg/ml, 612.22 ± 4.2 µg/ml, and 1210.30 ± 6.4 µg/ml respectively . Depending upon the cytotoxicity screening, HeLa cell line was considered for the further studies. Cell morphology study exhibited that LBE treated HeLa cells became round from normal spindle shape. DAPI staining showed that LBE treated nucleus became condensed and fragmented. DNA fragmentation at 230 and 300 base pair zone from agarose gel assay was observed. LBE induced ROS generation and reduced MMP. It up regulated the expression of apoptotic genes and p53 while down regulated Bcl2, pro-caspase 3 and pro caspase-9 gene. Cell cycle was arrested at G2/M checkpoint. Autophagic induction was exhibited by vacuole formation in treated cells. CSC population of treated cells was reduced and F-actin polymerization was observed in treated cells. In addition, LBE suppressed metastatic nature by inhibition of cell migration and colonization. The inhibition of growth of the tumors in HeLa cell-implanted mice showed that treatment with 50 mg LBE/kg of body weight of mice led to a marked reduction in the volume (93.22 ± 9.2 %) and weight (90.42 ±9.55 %) of the tumors. The GC-MS profile of LBE shows that out of 69 compounds, 9, 12-Octadecadienoic acid (Z, Z) and 8, (3.beta22E) are in a significantly higher proportion with the percentage peak area 22.13 and 19.72 respectively. Library search for bioactivity showed that these compounds are anti-cancerous and interestingly 4'-Hydroxy-6methoxyaurone binding with P-glycoprotein inhibits the cancer cells to become drug resistant. In conclusion, LBE is very prominent anti-cervical cancer having a lot of anti-cancerous compounds which are probably acting synergistically. This report of anti-ce...

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Autophagy‐Induced Apoptosis in Lung Cancer Cells by a Novel Digitoxin Analog

Cited by 26 publications

References 49 publications

2-Deoxy-d-Glucose and Its Analogs: From Diagnostic to Therapeutic Agents

2-Deoxy-d-Glucose and Its Analogs: From Diagnostic to Therapeutic Agents

Employing Metabolism to Improve the Diagnosis and Treatment of Pancreatic Cancer

Anti-cancer property of Lenzites betulina (L) Fr. on cervical cancer cell lines and its anti-tumor effect on HeLa-implanted mice

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