Suppressing autophagy enhances disulfiram/copper-induced apoptosis in non-small cell lung cancer

Wu, Xi; Xue, Xue; Wei, Lihui; Wang, Wenjing; Han, Jian; Sun, Xiaoxue; Zhang, Haotian; Liu, Yueyang; Che, Xiaohang; Yang, Jingyu; Wu, Chunfu

doi:10.1016/j.ejphar.2018.02.039

Cited by 55 publications

(42 citation statements)

References 33 publications

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“…It is known that the cytotoxic effect of thiocarbamates such as DDC and DSF is considerably enhanced in the presence of ions of copper and other metals of transient valence [21][22][23][24][25][26][27]. We showed that the enhancement of the cytotoxicity of DDC combined with B 12b did not depend on copper ions, although the effect of DDC alone as well as of DSF was strengthened many times by copper ions [20].…”

Section: Discussionmentioning

confidence: 75%

“…It is known that DTC produces either the antiapoptotic or the proapoptotic action depending on concentration, cell type, and the presence of metal ions [24,25,42]. The authors of most works concerned with the cytotoxic effect of DTC in combination with copper or zinc ions found that cell death occurred by apoptosis [24][25][26][27][42][43][44]; however, the data of other authors indicate that the cell death can occur by pathways other than apoptosis [30,45]. In our experiments, the combination DDC + B 12b also induced nonapoptotic cell death.…”

Section: Discussionmentioning

confidence: 99%

“…DDC, which is a chelator of metal ions, is used for detoxication after nickel and cadmium poisoning. It is believed that the cytotoxicity of DDC is mainly associated with its ability to chelate the transition metal ions, primarily copper and zinc [21][22][23][24][25][26][27]. Based on this feature, novel complexes of DDC and other DTC with metal ions for the application in antitumor therapy are being designed [28][29][30].…”

Section: Introductionmentioning

confidence: 99%

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Vitamin B12b Enhances the Cytotoxicity of Diethyldithiocarbamate in a Synergistic Manner, Inducing the Paraptosis-Like Death of Human Larynx Carcinoma Cells

et al. 2020

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We have shown that hydroxycobalamin (vitamin B12b) increases the toxicity of diethyldithiocarbamate (DDC) to tumor cells by catalyzing the formation of disulfiram (DSF) oxi-derivatives. The purpose of this study was to elucidate the mechanism of tumor cell death induced by the combination DDC + B12b. It was found that cell death induced by DDC + B12b differed from apoptosis, autophagy, and necrosis. During the initiation of cell death, numerous vacuoles formed from ER cisterns in the cytoplasm, and cell death was partially suppressed by the inhibitors of protein synthesis and folding, the IP3 receptor inhibitor as well as by thiols. At this time, a short-term rise in the expression of ER-stress markers BiP and PERK with a steady increase in the expression of CHOP were detected. After the vacuolization of the cytoplasm, functional disorders of mitochondria and an increase in the generation of superoxide anion in them occurred. Taken together, the results obtained indicate that DDC and B12b used in combination exert a synergistic toxic effect on tumor cells by causing severe ER stress, extensive ER vacuolization, and inhibition of apoptosis, which ultimately leads to the induction of paraptosis-like cell death.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Vitamin B12b Enhances the Cytotoxicity of Diethyldithiocarbamate in a Synergistic Manner, Inducing the Paraptosis-Like Death of Human Larynx Carcinoma Cells

et al. 2020

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“…Recent studies suggest that Cu-DSF may have strong anti-tumor activity through inhibition of the proteasome. The disadvantage, however, is that the Cu-DSF complex is poorly soluble in biological fl uid and unstable (12). Copper and its complexes in combination with other substances are also capable of affecting a wide variety of tumor cells, including cells that are resistant to a particular type of drug (13).…”

Section: Introductionmentioning

confidence: 99%

Schiff base Cu(II) complexes as inhibitors of proteasome in human cancer cells

Koňariková¹,

Frivaldska²,

Gbelcová³

et al. 2019

BLL

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BACKGROUND: It has been demonstrated that proteasome inhibitors might be potential anticancer drugs. The copper complexes can be used as specifi c proteasome inhibitors in tumor cells able to induce apoptosis by the ubiquitin-proteasome pathway. The goal of our study was to test the cytotoxic and proteasome inhibitory effects of fi ve Schiff base Cu(II) complexes -(4) on human lung carcinoma cells A549, cervix carcinoma cells HeLa and glioblastoma cells U-118MG. MATERIAL AND METHODS: For the cytotoxic analysis we used MTT test and for monitoring the proteasome inhibition western blot analysis. RESULTS: We have observed different cytotoxic effects of tested complexes on human cancer cells depending on the ligand present in their structure. Cu(II) complexes 4 and 5 were the most effective against A549 cells; all complexes were cytotoxic against HeLa cells and the complex 4 was the most effective against U-118MG. Moreover, we have detected the inhibition of the proteasome activity in human cancer cells A549 by Cu(II) complexes 1, 2 and 4 at IC 50 concentration. CONCLUSION: Results of our study suggest that isoquinoline-and imidazole-based copper complexes could be used as inhibitors of the proteasome system in cancer cells A549 (Tab. 1, Fig. 1, Ref. 26). Text in PDF www.elis.sk.

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“…The 5-year survival rate is less than l5%. The high mortality rate of lung cancer is related to the lack of early detection methods and poor treatment measures [ 2 – 5 ]. In order to improve survival rate, we must achieve early diagnosis and surgical treatment.…”

Section: Introductionmentioning

confidence: 99%

Methylenetetrahydrofolate Dehydrogenase 1 Silencing Expedites the Apoptosis of Non-Small Cell Lung Cancer Cells via Modulating DNA Methylation

Jiang

Chen

et al. 2018

Med Sci Monit

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BackgroundNon-small cell lung cancer (NSCLC) accounts for about 85% of all types of lung cancer. Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) is involved in DNA methylation, and DNA methylation is related to tumorigenesis. The role of MTHFD1 in NSCLC was examined in our study.Material/MethodsThe correlation between the expression of MTHFD1 and the clinicopathological features of patients diagnosed with lung cancer was investigated using the chi-square test. The viability and apoptosis of NCI-H1299 cells was respectively detected using cell counting kit-8 and flow cytometry assays. The expression levels of MTHFD1, apoptosis-related factors and DNA methyltransferase-related factors were assessed by quantitative real-time PCR (qRT-PCR) and western blot assays.ResultsWe found that MTHFD1 expression in the tumor tissues and cells was higher than that of adjacent normal tissues and cells. The survival time of patients with high MTHFD1 expression was shorter than those with low MTHFD1 expression. The expression level of MTHFD1 was related to tumor size, TNM stage, histologic grade, and metastasis, but not linked to gender and age. Besides, si-MTHFD1 significantly decreased the viability of cells in a time-dependent manner, and increased cell apoptosis. When cells were transfected with MTHFD1-siRNA, the levels of surviving and B-cell lymphoma-2 (Bcl-2) were attenuated, while p53 and Bcl-2 associated X protein (Bax) levels were enhanced. Moreover, si-MTHFD1 markedly downregulated the expression levels of DNA methyltransferase 1 (DNMT1), DNMT3a, and DNMT3b.ConclusionsCollectively, our results proved that MTHFD1 silencing obviously reduced the proliferation and enhanced the apoptosis of NSCLC via suppressing DNA methylation.

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Suppressing autophagy enhances disulfiram/copper-induced apoptosis in non-small cell lung cancer

Cited by 55 publications

References 33 publications

Vitamin B12b Enhances the Cytotoxicity of Diethyldithiocarbamate in a Synergistic Manner, Inducing the Paraptosis-Like Death of Human Larynx Carcinoma Cells

Vitamin B12b Enhances the Cytotoxicity of Diethyldithiocarbamate in a Synergistic Manner, Inducing the Paraptosis-Like Death of Human Larynx Carcinoma Cells

Schiff base Cu(II) complexes as inhibitors of proteasome in human cancer cells

Methylenetetrahydrofolate Dehydrogenase 1 Silencing Expedites the Apoptosis of Non-Small Cell Lung Cancer Cells via Modulating DNA Methylation

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