• BMB Reports
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• v.55 no.11
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• pp.547-552
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• 2022

Sorafenib, originally identified as an inhibitor of multiple oncogenic kinases, induces ferroptosis in hepatocellular carcinoma (HCC) cells. Several pathways that mitigate sorafenib-induced ferroptosis confer drug resistance; thus strategies that enhance ferroptosis increase sorafenib efficacy. Orphan nuclear receptor estrogen-related receptor γ (ERRγ) is upregulated in human HCC tissues and plays a role in cancer cell proliferation. The aim of this study was to determine whether inhibition of ERRγ with DN200434, an orally available inverse agonist, can overcome resistance to sorafenib through induction of ferroptosis. Sorafenib-resistant HCC cells were less sensitive to sorafenibinduced ferroptosis and showed significantly higher ERRγ levels than sorafenib-sensitive HCC cells. DN200434 induced lipid peroxidation and ferroptosis in sorafenib-resistant HCC cells. Mechanistically, DN200434 increased mitochondrial ROS generation by reducing glutathione/glutathione disulfide levels, which subsequently reduced mTOR activity and GPX4 levels. DN200434 induced amplification of the antitumor effects of sorafenib was confirmed in a tumor xenograft model. The present results indicate that DN200434 may be a novel therapeutic strategy to re-sensitize HCC cells to sorafenib.

• Clinical and Experimental Pediatrics
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• v.52 no.6
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• pp.696-700
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• 2009

Purpose : We screened more than 350 compounds with an endoperoxide ring structure in search of an anti-leukemic drug and found that compound 127 (c-127) could induce significant cytotoxicity in HL-60 cells. In this study, we investigated the molecular mechanisms of compound 127-induced antitumor activity on HL-60 cells. Methods : HL-60 cells were cultured in Rosewell Park Memorial Institute 1640 and cell viability was measured by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide], a tetrazole assay. Apoptosis was assessed by a DNA fragmentation test. Apoptotic machineries were determined by Western blot analysis. Results : C-127 could induce a cytotoxic effect at 24 h and apoptosis at 6 h, which was demonstrated with MTT assay and DNA fragmentation test, respectively. The apoptotic effect of this drug was caused by the activation of the intracellular caspase-8,3 activation, the cleavage of pro-apoptotic Bid, and the increase of c-Jun expression accompanied with JNK (Jun N-terminal kinases) phosphorylation. On the contrary, it increased the expression of anti-apoptotic Bcl-2 levels, leading to the induction of the induction of anti-apoptotic effect. Taken together, the present study demonstrated that c-127 was a potent inducer of cytotoxicity on HL-60 cells through apoptotic mechanisms, which included the activation of caspase family, the regulation of Bcl-2 family, and the activation of JNK signaling pathway. Conclusion : Our results suggest that c-127 has a strong antitumor activity through the regulation of various apoptotic machineries on HL-60 cells. The compound may be utilized as an effective and potentially therapeutic drug in leukemia.

• Korean Journal of Pharmacognosy
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• v.30 no.4
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• pp.404-408
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• 1999

SH2 domains and their associated catalytic or noncatalytic proteins constitute critical signal transduction targets for drug discovery. Grb2 associates with phosphotyrosine sites of the activated receptors or Shc via their SH2 domain to link receptor tyrosine kinases to ras signalling. Blocking of the Grb2-Shc complex may be to intervene the oncogenic signal transduction pathways and to develop a new antitumor drug. In the search for blockers of Grb2 SH2-Shc interaction, Lutein, a family of carotenoids, was isolated from the extract of the leaf of Agastache rugosa O. Kuntze as SH2 domain antagonists. The $IC_{50}$ of Lutein against Grb2-Shc binding was $6.8\;{\mu}M$.

• Development and Reproduction
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• v.21 no.2
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• pp.139-150
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• 2017

Metformin is the most commonly prescribed anti-diabetic drug with relatively minor side effect. Substantial evidence has suggested that metformin is associated with decreased cancer risk and anticancer activity against diverse cancer cells. The tyrosine kinase inhibitor imatinib has shown powerful activity for treatment of chronic myeloid leukemia and also induces growth arrest and apoptosis in colorectal cancer cells. In this study, we tested the combination of imatinib and metformin against HCT15 colorectal cancer cells for effects on cell viability, cell cycle and autophagy. Our data show that metformin synergistically enhances the imatinib cytotoxicity in HCT15 cells as indicated by combination and drug reduction indices. We also demonstrate that the combination causes synergistic down-regulation of pERK, cell cycle arrest in S and $G_2/M$ phases via reduction of cyclin B1 level. Moreover, the combination resulted in autophagy induction as revealed by increased acidic vesicular organelles and cleaved form of LC3-II. Inhibition of autophagic process by chloroquine led to decreased cell viability, suggesting that induction of autophagy seems to play a cell protective role that may act against anticancer effects. In conclusion, our present data suggest that metformin in combination with imatinib might be a promising therapeutic option in colorectal cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.15
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• pp.6343-6347
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• 2014

Multi-target drug design, in which drugs are designed as single molecules to simultaneously modulate multiple physiological targets, is an important strategy in the field of drug discovery. QT-011, a tamibarotene-furoxan derivative, was here prepared and proposed to exert synergistic effects on antileukemia by releasing nitric oxide and tamibarotene. Compared with tamibarotene itself, QT-011 displayed stronger antiproliferative effects on U937 and HL-60 cells and was more effective evaluated in a nude mice U937 xenograft model in vivo. In addition, QT-011 could release nitric oxide which might contribute to the antiproliferative activity. Autodocking assays showed that QT-011 fits well with the hydrophobic pocket of retinoic acid receptors. Taken together, these results suggest that QT-011 might be a highly effective derivative of tamibarotene and a potential candidate compound as antileukemia agent.

• Archives of Pharmacal Research
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• v.22 no.2
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• pp.151-156
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• 1999

Despite the impressive antitumor activity of cisplatin, two major limitations of the drug, that is severe side effects and drug-resistance of cancer cells, make its use difficult of r cancer therapy. These limitations have resulted in a greate deal of effort having been expended into structural modifications of cisplatin. In this study, we tested two novel cisplatin analogues, (CPA)2 Pt[DOLYM] (COMP-I) and (DACH)Pt[DOLYM] (CoMP-II), for the mode of cytotoxic action against human tumor cells comparing with cisplatin and carboplatin in vitro. These two novel analogues had considerable cytotoxic activities against five kinds of human solid tumor cells, and especially COMP-II was more effective on HCT15 colon cancer cells than other compounds. In addition, COMP-II had cytostatic activity at low concentrations (10~0.3${\mu}g/ml$), but other compounds revealed little effect on tumor growth at the low concentration.

• Journal of Microbiology and Biotechnology
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• v.32 no.6
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• pp.718-729
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• 2022

Esophageal squamous cell carcinoma (ESCC) is the most common primary esophageal malignancy with poor prognosis. Here, due to the necessity for exploring potential therapies against ESCC, we obtained the gene expression data on ESCC from the TCGA and GEO databases. Venn diagram analysis was applied to identify common targets. The protein-protein interaction network was constructed by Cytoscape software, and the hub targets were extracted from the network via cytoHubba. The potential hub nodes as drug targets were found by pharmacophore-based virtual screening and molecular modeling, and the antitumor activity was evaluated through in vitro studies. A total of 364 differentially expressed genes (DEGs) in ESCC were identified. Pathway enrichment analyses suggested that most DEGs were mainly involved in the cell cycle. Three hub targets were retrieved, including CENPF, CCNA2 (cyclin A), and CCNB1 (cyclin B1), which were highly expressed in esophageal cancer and associated with prognosis. Moreover, amentoflavone, a promising drug candidate found by pharmacophore-based virtual screening, showed antiproliferative and proapoptotic effects and induced G1 in esophageal squamous carcinoma cells. Taken together, our findings suggested that amentoflavone could be a potential cell cycle inhibitor targeting cyclin B1, and is therefore expected to serve as a great therapeutic agent for treating esophageal squamous cell carcinoma.

• The Korean Journal of Pharmacology
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• v.29 no.2
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• pp.283-295
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• 1993

Pt-complexes is currently one of the most compounds used in the treatment of solid tumors. However, its used is limited by severe side effects such as renal toxicity. Our platinum-based drug discovery program is aimed at developing drugs capable of diminishing toxicity and improving antitumor activity. We synthesized new Pt (II) complex analogues containing 1, 2-diaminocyclohexane (dach) as carrier ligand and 1, 3-bis (diphenylphosphino) propane (DPPP)/1,2-bis (diphenylphosphino) ethane (DPPE) as a leaving group. Furthermore, nitrate was added to improve the solubility. A new series of (KHPC-001) [Pt (trans-1-dach)(DPPP)] $2NO_3$ and (KHPC-002) [Pt (trans-1-dach)(DPPE)] $2NO_3$ were synthesized and characterized by their elemental analysis and by various spectroscopic techniques [infrared (IR), $^{13}carbon$ nuclear magnetic resonance (NMR)]. KHPC-001 and KHPC-002 demonstrated acceptable antitumor activity aganist P-388, L-1210 lymphocytic leukemia cells and significant activity as compared with that of cisplatin. The toxicity of KHPC-001 and KHPC-002 was found quite less than that of cisplatin using MTT, $[^3H]$ thymidine uptake and glucose consumption tests in rabbit proximal tubule cells and human kidney cortical cells.

• The Korean Journal of Pharmacology
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• v.32 no.1
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• pp.93-102
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• 1996

Platinum coordination complexes are currently one of the most compounds used in the treatment of solid tumors. However, its use is limited by severe side effects such as nephrotoxicity. Our platinum-based drug discovery program is aimed at developing drugs capable of diminishing toxicity and broadening the clinical spectrum of activity of cisplatin. We synthesized new Pt(II) complex analogue containing 1,2-diaminocyclohexane (dach) as carrier ligand and 1,3-bis(diphenyl phosphino)propane (DPPP) as a leaving group. Furthermore, nitrate was added to improve the solubility. A new series of PC-1 [Pt(cis-dach) (DPPP)]. $2NO_3_2$ was synthesized and characterized by their elemental analysis and by various spectroscopic techniques [infrared (IR), $^{13}carbon$ nuclear magnetic resonance (NMR)]. PC-1 was demonstrated acceptable antitumor activity aganist SKOV -3, OVCAR-3 human ovarian adenocarcinomacells and significant activity as compared with that of cisplatin. The toxicity of PC-1 was found quite less than that of cisplatin using MTT, $[^3H]thymidine$ uptake and glucose consumption tests in rabbit proximal tubule cells, human kidney cortical cells and human renal cortical tissues. Based on these results, this novel platinum compound represent a valuable lead in the development of a new anticancer chemotherapeutic agent capable of improving antitumor activity and low toxicity.

• Archives of Pharmacal Research
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• v.21 no.6
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• pp.749-752
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• 1998

Six 3-dialkylaminomethyl-1-azaanthraquinones and five 4-dialkylaminomethyl-1-azaanthraquinones were synthesized and evaluated in vitro cytotoxicity against four human can cer cell lines. The compounds retained much of their cytotoxic activity against the multi-drug-resistant cell line (KB-V-1) as shown by resistance index.