Acidic pH of Tumor Microenvironment Enhances Cytotoxicity of the Disulfiram/Cu&lt;sup&gt;2+&lt;/sup&gt; Complex to Breast and Colon Cancer Cells

Navrátilová, Jarmila; Hankeová, Tereza; Beneš, Petr; Šmarda, Jan

doi:10.1159/000353915

Cited by 26 publications

(18 citation statements)

References 87 publications

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“…2). In addition to boosting tissue invasiveness, migratory potential [245,268] and altering drug sensitivity [269,270], an acidic culture condition can have profound effects on other aspects of cancer. Changes to metabolic patterns have been observed when cancer cells are cultured in acidic conditions, with a switch from reliance on aerobic glycolysis and production of lactic acid under a physiological pH to a reversion back to oxidative phosphorylation in an acidic environment [271].…”

Section: Acidic Culture Conditionsmentioning

confidence: 99%

Lessons from patient-derived xenografts for better in vitro modeling of human cancer

Choi¹,

Lin²,

Gout³

et al. 2014

Advanced Drug Delivery Reviews

157

134

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The development of novel cancer therapeutics is often plagued by discrepancies between drug efficacies obtained in preclinical studies and outcomes of clinical trials. The inconsistencies can be attributed to a lack of clinical relevance of the cancer models used for drug testing. While commonly used in vitro culture systems are advantageous for addressing specific experimental questions, they are often gross, fidelity-lacking simplifications that largely ignore the heterogeneity of cancers as well as the complexity of the tumor microenvironment. Factors such as tumor architecture, interactions among cancer cells and between cancer and stromal cells, and an acidic tumor microenvironment are critical characteristics observed in patient-derived cancer xenograft models and in the clinic. By mimicking these crucial in vivo characteristics through use of 3D cultures, co-culture systems and acidic culture conditions, an in vitro cancer model/microenvironment that is more physiologically relevant may be engineered to produce results more readily applicable to the clinic.

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Section: Acidic Culture Conditionsmentioning

confidence: 99%

Lessons from patient-derived xenografts for better in vitro modeling of human cancer

Choi¹,

Lin²,

Gout³

et al. 2014

Advanced Drug Delivery Reviews

157

134

View full text Add to dashboard Cite

show abstract

“…Six hours later, the medium was replaced with fresh one and cells were pretreated with 25 μM copper sulfate or left untreated for 24 h. Then, the cells were exposed to 25 μM wedelolactone or DMSO for 10 h in fresh media. Cells were harvested and cell lysates prepared as described previously [39]. Briefly, pelleted cells were washed twice with 1 × PBS and 1.0 × 10 6 cell were lysed in a mixture of 3 M HCl/10% trichloroacetic acid at room temperature for 3 h followed by incubation at 70 °C for 5 h. The lysate was centrifuged (600 g/5 min) to remove cell debris and the total amount of copper in supernatant was determined by substrate-assisted laser desorption inductively-coupled plasma mass spectrometry (SALD ICP MS) [40].…”

Section: Methodsmentioning

confidence: 99%

Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer Cells

Nehybová

Šmarda

Daniel

et al. 2017

IJMS

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Wedelolactone is a multi-target natural plant coumestan exhibiting cytotoxicity towards cancer cells. Although several molecular targets of wedelolactone have been recognized, the molecular mechanism of its cytotoxicity has not yet been elucidated. In this study, we show that wedelolactone acts as an inhibitor of chymotrypsin-like, trypsin-like, and caspase-like activities of proteasome in breast cancer cells. The proteasome inhibitory effect of wedelolactone was documented by (i) reduced cleavage of fluorogenic proteasome substrates; (ii) accumulation of polyubiquitinated proteins and proteins with rapid turnover in tumor cells; and (iii) molecular docking of wedelolactone into the active sites of proteasome catalytic subunits. Inhibition of proteasome by wedelolactone was independent on its ability to induce reactive oxygen species production by redox cycling with copper ions, suggesting that wedelolactone acts as copper-independent proteasome inhibitor. We conclude that the cytotoxicity of wedelolactone to breast cancer cells is partially mediated by targeting proteasomal protein degradation pathway. Understanding the structural basis for inhibitory mode of wedelolactone might help to open up new avenues for design of novel compounds efficiently inhibiting cancer cells.

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“…Although survival rates of patients with CRC with early‐stage disease have significantly improved in the last few years because of the advances in diagnosis and treatment, clinical outcomes for patients with advanced CRC still remains poor . An increasing body of evidence suggests that genetic alterations and tumor microenvironment play important roles in CRC development . Of those findings, hypoxia and autophagy are widely investigated in colorectal tumor.…”

Section: Introductionmentioning

confidence: 99%

miR‐20a inhibits hypoxia‐induced autophagy by targeting ATG5/FIP200 in colorectal cancer

Che

Wang

Huang

et al. 2019

Molecular Carcinogenesis

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Autophagy is a highly conserved lysosome‐mediated protective cellular process in which cytosolic components, including damaged organelles and long‐lived proteins, are cleared. Many studies have shown that autophagy was upregulated in hypoxic regions. However, the precise molecular mechanism of hypoxia‐induced autophagy in colorectal cancer (CRC) is still elusive. In this study, we found that miR‐20a was significantly downregulated under hypoxia in colon cancer cells, and overexpression of miR‐20a alleviated hypoxia‐induced autophagy. Moreover, miR‐20a inhibits the hypoxia‐induced autophagic flux by targeting multiple key regulators of autophagy, including ATG5 and FIP200. Furthermore, by dual‐luciferase assay we demonstrated that miR‐20a directly targeted the 3′‐untranslated region of ATG5 and FIP200, regulating their messenger RNA and protein levels. In addition, reintroduction of exogenous ATG5 or FIP200 partially reversed miR‐20a‐mediated autophagy inhibition under hypoxia. A negative correlation between miR‐20a and its target genes is observed in the hypoxic region of colon cancer tissues. Taken together, our findings suggest that hypoxia‐mediated autophagy was regulated by miR‐20a/ATG5/FI200 signaling pathway in CRC. miR‐20a‐mediated autophagy defect that might play an important role in hypoxia‐induced autophagy during colorectal tumorigenesis.

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Acidic pH of Tumor Microenvironment Enhances Cytotoxicity of the Disulfiram/Cu<sup>2+</sup> Complex to Breast and Colon Cancer Cells

Cited by 26 publications

References 87 publications

Lessons from patient-derived xenografts for better in vitro modeling of human cancer

Lessons from patient-derived xenografts for better in vitro modeling of human cancer

Wedelolactone Acts as Proteasome Inhibitor in Breast Cancer Cells

miR‐20a inhibits hypoxia‐induced autophagy by targeting ATG5/FIP200 in colorectal cancer

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