Small-molecule anticancer agents kill cancer cells by harnessing reactive oxygen species in an iron-dependent manner

2018 ◽  
Vol 16 (9) ◽  
pp. 1465-1479 ◽  
Author(s):  
Sara R. Fedorka ◽  
Kevin So ◽  
Ayad A. Al-Hamashi ◽  
Ibtissam Gad ◽  
Ronit Shah ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cancer Cells ◽  
Cell Lines ◽  
Small Molecule ◽  
Anticancer Agents ◽  
Reactive Oxygen ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Open Chain ◽  
New Class

In the course of generating a library of open-chain epothilones, we discovered a new class of small molecule anticancer agents that has no effect on tubulin but instead kills selected cancer cell lines by harnessing reactive oxygen species in an iron-dependent manner.

scholarly journals Drug-Like Small Molecule HSP27 Functional Inhibitor Sensitizes Lung Cancer Cells to Gefitinib or Cisplatin by Inducing Altered Cross-Linked Hsp27 Dimers

Pharmaceutics ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 630
Author(s):  
Hawon Yoo ◽  
Seul-Ki Choi ◽  
Jaeok Lee ◽  
So Hyeon Park ◽  
You Na Park ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Cell Lines ◽  
Small Molecule ◽  
Anticancer Agents ◽  
Tumor Growth Inhibition ◽  
Dependent Manner ◽  
Hsp27 Expression ◽  
Cancer Aggressiveness

Relationships between heat shock protein 27 (HSP27) and cancer aggressiveness, metastasis, drug resistance, and poor patient outcomes in various cancer types including non-small cell lung cancer (NSCLC) were reported, and inhibition of HSP27 expression is suggested to be a possible strategy for cancer therapy. Unlike HSP90 or HSP70, HSP27 does not have an ATP-binding pocket, and no effective HSP27 inhibitors have been identified. Previously, NSCLC cancer cells were sensitized to radiation and chemotherapy when co-treated with small molecule HSP27 functional inhibitors such as zerumbone (ZER), SW15, and J2 that can induce abnormal cross-linked HSP27 dimer. In this study, cancer inhibition effects of NA49, a chromenone compound with better solubility, longer circulation time, and less toxicity than J2, were examined in combination with anticancer drugs such as cisplatin and gefitinib in NSCLC cell lines. When the cytotoxic drug cisplatin was treated in combination with NA49 in epidermal growth factor receptors (EGFRs) WT cell lines, sensitization was induced in an HSP27 expression-dependent manner. With gefitinib treatment, NA49 showed increased combination effects in both EGFR WT and Mut cell lines, also with HSP27 expression-dependent patterns. Moreover, NA49 induced sensitization in EGFR Mut cells with a secondary mutation of T790M when combined with gefitinib. Augmented tumor growth inhibition was shown with the combination of cisplatin or gefitinib and NA49 in nude mouse xenograft models. These results suggest the combination of HSP27 inhibitor NA49 and anticancer agents as a candidate for overcoming HSP27-mediated drug resistance in NSCLC patients.

A small molecule that induces reactive oxygen species via cellular glutathione depletion

2014 ◽  
Vol 463 (1) ◽  
pp. 53-63 ◽  
Author(s):  
Tatsuro Kawamura ◽  
Yasumitsu Kondoh ◽  
Makoto Muroi ◽  
Makoto Kawatani ◽  
Hiroyuki Osada
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Lines ◽  
Cancer Cell ◽  
Small Molecule ◽  
Reactive Oxygen ◽  
Cancer Cell Lines ◽  
Glutathione Depletion ◽  
Oxygen Species ◽  
Chemical Library ◽  
Cytotoxic Compound

A new cytotoxic compound was found in our chemical library. We revealed that the compound induced reactive oxygen species through glutathione depletion. Moreover, the compound was effective against several cancer cell lines including those harbouring KRAS.

scholarly journals Curcuma raktakanda Induces Apoptosis and Suppresses Migration in Cancer Cells: Role of Reactive Oxygen Species

Biomolecules ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 159 ◽  
Author(s):  
Mishra ◽  
Verma ◽  
Rai ◽  
Awasthee ◽  
Arya ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Ethyl Acetate ◽  
Cancer Cells ◽  
Reactive Oxygen Species Generation ◽  
Glioma Cells ◽  
Reactive Oxygen ◽  
Acetone Extract ◽  
Breast Cancer Cell Lines ◽  
Dependent Manner ◽  
Oxygen Species

Although over 100 species of Curcuma are reported, only Curcuma longa is extensively studied. Curcuma raktakanda, a poorly studied species, is most commonly distributed in the Kerala state of India. For the first time, we examined the efficacy of different fractions (acetone, hexane, and ethyl acetate) of C. raktakanda against glioma, cervical, and breast cancer cell lines. As determined by mitochondrial reductase activity assay, the viability of cancer cells was decreased in a concentration-dependent manner by the three fractions. The half maximal inhibitory concentration (IC-50) values after the treatment of C-6 glioma cells for 48 h was found to be 32.97 µg/mL (acetone extract), 40.63 µg/mL (hexane extract), and 51.65 µg/mL (ethyl acetate extract). Of the three fractions, the acetone fraction was more effective. The long-term colony formation of cancer cells was significantly suppressed by the acetone fraction. Analyses using DAPI (4′,6-diamidino-2-phenylindole) staining, AO/PI (acridine orange/propidium iodide) staining, DNA laddering, and sub-G1 population revealed that the acetone extract induced apoptosis in glioma cells. The extract induced reactive oxygen species generation and suppressed the expression of cell survival proteins. The migration of cancer cells was also suppressed by the acetone extract. The gas chromatography-mass spectrometry (GC-MS) analysis indicated that tetracontane, dotriacontane, hexatriacontane, pentacosane, hexacosane, and eicosane are the major components in the acetone extract. Collectively, the extract from C. raktakanda exhibited anti-carcinogenic activities in cancer cells. We are exploring whether the phytoconstituents, individually, or collectively contribute to the anti-cancer activities of C. raktakanda.

scholarly journals Serine/Threonine Kinase 17A Is a Novel p53 Target Gene and Modulator of Cisplatin Toxicity and Reactive Oxygen Species in Testicular Cancer Cells

2011 ◽  
Vol 286 (22) ◽  
pp. 19381-19391 ◽  
Author(s):  
Pingping Mao ◽  
Mary P. Hever ◽  
Lynne M. Niemaszyk ◽  
Jessica M. Haghkerdar ◽  
Esty G. Yanco ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Testicular Cancer ◽  
Cancer Cells ◽  
Target Gene ◽  
Reactive Oxygen ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Antioxidant Genes ◽  
Ec Cells ◽  
P53 Target Gene

Testicular cancer is highly curable with cisplatin-based therapy, and testicular cancer-derived human embryonal carcinoma (EC) cells undergo a p53-dominant transcriptional response to cisplatin. In this study, we have discovered that a poorly characterized member of the death-associated protein family of serine/threonine kinases, STK17A (also called DRAK1), is a novel p53 target gene. Cisplatin-mediated induction of STK17A in the EC cell line NT2/D1 was prevented with p53 siRNA. Furthermore, STK17A was induced with cisplatin in HCT116 and MCF10A cells but to a much lesser extent in isogenic p53-suppressed cells. A functional p53 response element that binds endogenous p53 in a cisplatin-dependent manner was identified 5 kb upstream of the first coding exon of STK17A. STK17A is not present in the mouse genome, but the closely related gene STK17B is induced with cisplatin in mouse NIH3T3 cells, although this induction is p53-independent. Interestingly, in human cells containing both STK17A and STK17B, only STK17A is induced with cisplatin. Knockdown of STK17A conferred resistance to cisplatin-induced growth suppression and apoptotic cell death in EC cells. This was associated with the up-regulation of detoxifying and antioxidant genes, including metallothioneins MT1H, MT1M, and MT1X that have previously been implicated in cisplatin resistance. In addition, knockdown of STK17A resulted in decreased cellular reactive oxygen species, whereas STK17A overexpression increased reactive oxygen species. In summary, we have identified STK17A as a novel direct target of p53 and a modulator of cisplatin toxicity and reactive oxygen species in testicular cancer cells.

scholarly journals Autophagy inhibition enhances Matrine derivative MASM induced apoptosis in cancer cells via a mechanism involving reactive oxygen species-mediated PI3K/Akt/mTOR and Erk/p38 signaling

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Yuming Zou ◽  
Melika Sarem ◽  
Shengnan Xiang ◽  
Honggang Hu ◽  
Weidong Xu ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cancer Cells ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Reactive Oxygen ◽  
Cancer Cell Line ◽  
Cancer Cell Lines ◽  
Oxygen Species ◽  
Induced Apoptosis

Abstract Background In the quest for new anti-cancer drugs, the drug discovery process has shifted to screening of active ingredients in traditional eastern medicine. Matrine is an active alkaloid isolated from plants of the Sophora genus used in traditional Chinese herbal medicine that exhibits a wide spectrum of biological properties and has a potential as an anti-proliferative agent. In this study, we investigated the anticancer property of MASM, ([(6aS, 10S, 11aR, 11bR, 11cS)210-Methylamino-dodecahydro-3a, 7a-diaza-benzo (de)anthracene-8-thione]), a potent derivative of matrine. Methods Four epithelial cancer cell lines representing the dominant cancers, namely: A549 (non-small-cell lung cancer cell line), MCF-7 and MDA-MB-231 (breast cancer cell lines), and Hela (cervical cancer cell line) were employed, and the mechanistic underpinning of MASM-induced apoptosis was investigated using flow cytometry, western blot and immunofluorescence. Results MASM, induced apoptosis via caspase 3 dependent and independent pathways, and autophagy in all the four cancer cell lines, but post-EMT (epithelial mesenchymal transition) cells showed greater sensitivity to MASM. Scavenging reactive oxygen species using N-acetylcysteine rescued all cancer cell lines from apoptosis and autophagy. Mechanistic analysis revealed that MASM induced autophagy involves inhibition of Akt signaling and the activation of Erk and p38 signaling, and inhibition of autophagy further enhanced the apoptosis induced by MASM. Conclusions These results indicate that MASM possesses potency against cancer cells and modulating autophagy during MASM administration could be used to further enhance its therapeutic effects.

scholarly journals Emodin induced necroptosis and inhibited glycolysis in the renal cancer cells by enhancing ROS

2020 ◽  
Author(s):  
Ke-jie Wang ◽  
Xiang-yu Meng ◽  
Jun-feng Chen ◽  
Kai-yun Wang ◽  
Cheng Zhou ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Flow Cytometry ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Renal Cancer ◽  
Reactive Oxygen ◽  
Chinese Herbs ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Flow Cytometry Assay

Abstract Background: Renal cell carcinoma (RCC) is a tumor with unpredictable presentation and poor clinical outcome. RCC is always resistant to chemotherapy, radiation, and weakly sensitive to immunotherapeutic agents. Therefore, novel agents and approaches are urgently needed for the treatment of RCC. Emodin, an anthraquinone compound extracted from rhubarb and other traditional Chinese herbs, has been implicated in a wide variety of pharmacological effects, such as anti-inflammatory, antiviral, and antitumor activities. However，its role in RCC remains unkown. Methods: Flow cytometry assay and lactate dehydrogenase release assay were used to detect the cell death. Reactive oxygen species was tested by the dye MitoSox and DCFH-DA. Glucose-6-phosphate, pyruvate and ATP level were measured to evaluate the glycolysis process. Western blot was used to detect protein expression. Results: Emodin effectively killed renal cancer cells without significant toxicity to normal renal tubular epithelial cell. Flow cytometry assay with Annexin V-FITC and PI demonstrated that emodin induces necroptosis, but not apoptosis, in renal cancer cells. Meanwhile, the phosphorylation levels of RIP1 and MLKL, the key necroptosis-related proteins, were significantly increased. To explore how emodin inhibits kidney tumor growth, reactive oxygen species (ROS) levels were tested and the levels of ROS increased upon emodin treatment in a dose-dependent manner. Further studies demonstrated that emodin induced necroptosis through ROS-mediated activation of JNK signaling pathway, and also inhibited glycolysis by down-regulation GLUT1 by ROS-mediated inactivation of PI3K/AKT signaling pathway. Conclusion: These findings revealed the potential mechanisms by which emodin suppresses renal cancer cell growth, and will help develop novel therapeutic approaches for patients with JNK- or PI3K/AKT-dysregulated renal cancer.

Apoptosis induced by emodin is associated with alterations of intracellular acidification and reactive oxygen species in EC-109 cellsThis paper is one of a selection of papers published in this special issue entitled “Second International Symposium on Recent Advances in Basic, Clinical, and Social Medicine” and has undergone the Journal's usual peer review process.

2010 ◽  
Vol 88 (4) ◽  
pp. 767-774 ◽  
Author(s):  
Q. J. Wang ◽  
X. B. Cai ◽  
M. H. Liu ◽  
H. Hu ◽  
X. J. Tan ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Flow Cytometry ◽  
Cancer Cells ◽  
Morphological Changes ◽  
Peer Review Process ◽  
Reactive Oxygen ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Fluorescence Measurements ◽  
Esophagus Carcinoma

Emodin (1,3,8-trihydroxy-6-methylanthraquinone), a natural anthraquinone derivative found in several herbal medicines, is highly active in suppressing the proliferation of various tumor cells such as breast, hepatocellular, and lung cancer cells under in vitro conditions. The mechanism of emodin-induced apoptosis in esophagus carcinoma cells, EC-109, is not completely understood. In this study, EC-109 cells treated with emodin underwent rapid apoptosis as judged by morphological changes and flow cytometry analysis. The addition of emodin to EC-109 cells led to the inhibition of growth in a time- and dose-dependent manner. Fluorescence measurements of cells indicated that the intracellular pH (pHi) decreased significantly by 0.47–0.78 units. The results obtained from flow cytometry suggested that bursts of reactive oxygen species took place after the application of emodin. The present study indicates that emodin may be a strong anticancer drug against esophagus cancer cells by causing various early events leading to growth inhibition, including the production of reactive oxygen species and decrease of pHi, which may result in cellular apoptosis.

Platinum complexes as light promoted anticancer agents: a redefined strategy for controlled activation

2016 ◽  
Vol 45 (48) ◽  
pp. 19157-19171 ◽  
Author(s):  
Koushambi Mitra
Keyword(s):  
Reactive Oxygen Species ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Light Exposure ◽  
Reactive Oxygen ◽  
Platinum Complexes ◽  
Oxygen Species

Platinum complexes can act as prodrugs which are non-cytotoxic in the dark but generate active platinum(ii) species and lethal reactive oxygen species on light exposure only in cancer cells, therefore leaving healthy cells unaffected.

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