Loss of Mitochondrial DNA by Gemcitabine Triggers Mitophagy and Cell Death.

Loss of Mitochondrial DNA by Gemcitabine Triggers Mitophagy and Cell Death. Biol Pharm Bull. 2019;42(12):1977-1987 Authors: Inamura A, Muraoka-Hirayama S, Sakurai K Abstract Gemcitabine (2,2-difluorodeoxycytidine nucleic acid), an anticancer drug exhibiting a potent ability to kill cancer cells, is a frontline chemotherapy drug. Although some chemotherapeutic medicines are known to induce nuclear DNA damage, no investigation into mitochondrial DNA (mtDNA) damage currently exists. When we treated insulinoma pancreatic β-cells (line INS-1) with high mitochondrial activity with gemcitabine for 24 h, the mtDNA contents were decreased. Gemcitabine induced a decrease in the number of mitochondria and the average potential of mitochondrial membrane in the cell but increased the superoxide anion radical levels. We observed that treatment with gemcitabine to induce cell death accompanied by autophagy-related protein markers, Atg5 and Atg7; these were significantly prevented by the autophagy inhibitors. The localization of Atg5 co-occurred with the location of mitochondria with membranes having high potential and mitophagy in cells treated with gemcitabine. The occurrence of mitophagy was inhibited by the inhibitors of the phosphatidylinositol 3-kinase/Akt pathway. Our results led us to the conclusion that gemcitabine induced cell death through mitophagy with the loss of mtDNA. These findings may provide a rationale for the combination of mtDNA damage ...
Source: Biological and Pharmaceutical Bulletin - Category: Drugs & Pharmacology Authors: Tags: Biol Pharm Bull Source Type: research

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Gemcitabine (GEM)-based chemotherapy is the standard regimen for the treatment of pancreatic cancer (PC). However, chemoresistance is a major challenge in PC treatment. Reliable biomarkers are urgently needed to predict the response to GEM-based therapies. GEM-sensitive (GEM-S) and GEM-resistant (GEM-R) pancreatic carcinoma xenograft models were established, and GEM monotherapy and GEM plus nanoparticle albumin-bound paclitaxel (nab-PTX) doublet therapy were administered to GEM-S/R tumor-bearing mice. Metabolomic mass spectrometry (MS) analysis of serum, liver, and tumor samples was performed using an ultraperformance liqu...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
ConclusionWhile a timely work-up of advanced PC patients remains important, delays in treatment initiation due to repeated biopsies, inclusion in a clinical study or transfer to a specialized cancer center appear to be justified in light of the absence of a strong adverse effect of prolonged TTI on prognosis in advanced PC patients.
Source: Journal of Cancer Research and Clinical Oncology - Category: Cancer & Oncology Source Type: research
This study aimed to evaluate the clinical outcomes, toxicity, and prognostic factors of SBRT combined with gemcitabine plus capecitabine (GEM-CAP) in treating locally advanced pancreatic cancer (LAPC).MethodsA total of 56 patients with LAPC treated with SBRT combined with GEM-CAP were reviewed from October 2010 to October 2016. The median total prescription dose at five fractions was 40  Gy (30–50 Gy). The patients were subjected to two cycles of GEM-CAP before SBRT. GEM-CAP chemotherapy was then offered for four cycles or until disease tolerance or progression. The primary endpoints included overall surviv...
Source: Journal of Cancer Research and Clinical Oncology - Category: Cancer & Oncology Source Type: research
er Arthur A major impediment to successful cancer treatment is the inability of clinically available drugs to kill drug-resistant cancer cells. We recently identified metabolically stable L-glucosamine-based glycosylated antitumor ether lipids (GAELs) that were cytotoxic to chemotherapy-resistant cancer cells. In the absence of commercially available L-glucosamine, many steps were needed to synthesize the compound and the overall yield was poor. To overcome this limitation, a facile synthetic procedure using commercially available L-sugars including L-rhamnose and L-glucose were developed and the L-GAELs tested for ...
Source: Molecules - Category: Chemistry Authors: Tags: Article Source Type: research
Contributors : Daniel Baumann ; Rienk OffringaSeries Type : Expression profiling by arrayOrganism : Mus musculusCancer types with lower mutational load and a non-permissive tumor microenvironment are intrinsically resistant to immune checkpoint blockade. While the combination of cytostatic drugs and immunostimulatory antibodies constitutes an attractive concept for overcoming this refractoriness, suppression of immune cell function by cytostatic drugs may limit therapeutic efficacy. Here we show that targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) does not impair dendritic cell-mediated T-cell p...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by array Mus musculus Source Type: research
Conclusion: It may be employed either alone or in combination with cryotherapy, existing chemotherapy, bypass surgery or radiations to achieve the optimal results in these patients. Nevertheless, there is a need to formulate a uniform dose and procedure to achieve homogeneity and develop references for clinical practices. PMID: 31977258 [PubMed - as supplied by publisher]
Source: International Journal of Radiation Biology - Category: Radiology Tags: Int J Radiat Biol Source Type: research
Conclusion: Locoregional peritoneal heating with the AMC-8 system yields more favorable heating patterns compared to other clinically used locoregional heating devices. Therefore, results of this study may promote the use of the AMC-8 system for locoregional hyperthermia in future multidisciplinary studies for treatment of PC. PMID: 31969039 [PubMed - in process]
Source: International Journal of Hyperthermia - Category: Internal Medicine Tags: Int J Hyperthermia Source Type: research
sin Okada Yamada Dapagliflozin, empagliflozin, tofogliflozin, selective inhibitors of sodium-glucose cotransporter 2 (SGLT2), is used clinically to reduce circulation glucose levels in patients with type 2 diabetes mellitus by blocking the reabsorption of glucose by the kidneys. Dapagliflozin is metabolized and inactivated by UGT1A9. Empagliflozin is metabolized and inactivated by UGT1A9 and by other related isoforms UGT2B7, UGT1A3, and UGT1A8. Tofogliflozin is metabolized and inactivated by five different enzymes CYP2C18, CYP3A4, CYP3A5, CYP4A11, and CYP4F3. Dapagliflozin treatment of HCT116 cells, which express...
Source: Molecules - Category: Chemistry Authors: Tags: Article Source Type: research
ConclusionThe results are encouraging, suggesting that SBRT has a significant role in the management of these patients and further studies will be necessary to prove these findings.
Source: Clinical and Translational Oncology - Category: Cancer & Oncology Source Type: research
Authors: Nielsen MFB, Mortensen MB, Sørensen MD, Wirenfeldt M, Kristensen BW, Schrøder HD, Pfeiffer P, Detlefsen S Abstract Pancreatic ductal adenocarcinoma (PC) is characterized by a highly fibrotic desmoplastic stroma. Subtypes of cancer-associated fibroblasts (CAFs) have been identified in chemotherapy-naïve PC (CTN-PC), but their precise functions are still unclear. Our knowledge regarding the properties of CAFs in the regressive stroma after neoadjuvant treatment (NAT) of PC (NAT-PC) is particularly limited. We aimed to examine the marker phenotypic properties of CAFs in the regressive strom...
Source: Histology and Histopathology - Category: Cytology Tags: Histol Histopathol Source Type: research
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