Su-Nam Kim

Sargaquinoic acid and sargahydroquinoic acid from Sargassum yezoense stimulate adipocyte differentiation through PPARα/γ activation in 3T3-L1 cells

We screened active compounds from natural marine products able to increase PPARα/γ transcriptional activity. Sargaquinoic acid (SQA) and sargahydroquinoic acid (SHQA) from Sargassum yezoense were identified as novel PPARα/γ dual agonists. The binding affinity of SQA with PPARγ was higher than that of the specific PPARγ agonist troglitazone, leading to an activation of PPARγ transcriptional activity. In parallel, treatment of 3T3‐L1 cells with SQA and SHQA led to an increase in adipocyte differentiation and increased expression of adipogenic marker genes such as aP2, PPARγ, resistin, adiponectin, C/EBPα and Glut4. Collectively, our data suggest that SQA and SHQA are novel PPARα/γ dual agonists and may be beneficial for reducing insulin resistance through regulation of adipogenesis.

Inhibitory effect of chalcones and their derivatives from Glycyrrhiza inflata on protein tyrosine phosphatase 1B

Compounds (1-6) isolated from the CH(2)Cl(2) extract of Glycyrrhiza inflata and semisynthetic licochalcone A derivatives (7-14) were evaluated for their protein tyrosine phosphatase 1B (PTP1B) inhibitory activities. Licochalcones A (4) and E (6), each with an allyl group at position 5 in the B ring exhibited significant inhibitory effects. Licochalcone A derivative 7, the most potent among the series, had an IC(50) value of 11.7+/-2.0 microM, ca. twofold better than that of licochalcone A (4).

Involvement of HDAC1 in E-cadherin expression in prostate cancer cells; its implication for cell motility and invasion.

In this study, we investigate the molecular mechanism by which histone deacetylase (HDAC) inhibitors exert anti-invasiveness effect against prostate cancer cells. We first evaluate the growth inhibition effect of HDAC inhibitors in prostate cancer cells, which is accompanied by induction of p21(WAF1) expression and accumulation of acetylated histones. And we found that the migration and invasion of prostate cancer cells is strongly inhibited by treatment with HDAC inhibitors. In parallel, E-cadherin level is highly up-regulated in HDAC inhibitor-treated prostate cancer cells. And siRNA knockdown of E-cadherin significantly diminishes the anti-invasion effect of HDAC inhibitors, indicating that E-cadherin overexpression is one of possible mechanism for anti-invasion effect of HDAC inhibitors. Furthermore, specific downregulation of HDAC1, but not HDAC2, causes E-cadherin expression and subsequent inhibition of cell motility and invasion. Collectively, our data demonstrate that HDAC1 is a major repressive enzyme for E-cadherin expression as well as HDAC inhibitor-mediated anti-invasiveness.

Synergistic effect of curcumin on epigallocatechin gallate-induced anticancer action in PC3 prostate cancer cells

Epigallocatechin gallate (EGCG) and curcumin are well known to naturally-occurring anticancer agents. The aim of this study was to verify the combined beneficial anticancer effects of curcumin and EGCG on PC3 prostate cancer cells, which are resistant to chemotherapy drugs and apoptosis inducers. EGCG showed weaker inhibitory effect on PC3 cell proliferation than two other prostate cancer cell lines, LNCaP and DU145. Co-treatment of curcumin improved antiproliferative effect of EGCG on PC3 cells. The protein expressions of p21 were significantly increased by the co-treatment of EGCG and curcumin, whereas it was not changed by the treatment with each individual compound. Moreover, treatments of EGCG and curcumin arrested both S and G2/M phases of PC3 cells. These results suggest that the enhanced inhibitory effect of EGCG on PC3 cell proliferation by curcumin was mediated by the synergic up-regulation of p21-induced growth arrest and followed cell growth arrest. [BMB Reports 2015; 48(8): 461-466]

HDAC inhibitors downregulate MRP2 expression in multidrug resistant cancer cells: implication for chemosensitization.

Although histone deacetylase (HDAC) inhibitors are emerging as a promising class of cancer chemotherapeutic agents, their effects on multidrug resistance (MDR) are poorly understood. In this study, we investigated whether HDAC inhibitors overcome MDR phenotype. HDAC inhibitors suppress the growth of both MDR positive cancer cells KBV20C and its parental cells KB with similar potencies. In parallel, histone acetylation and p21WAF1 expression by the HDAC inhibitors were similarly increased in both cell types, indicating that these HDAC inhibitors are poor substrates of ABC drug transporters and effective in MDR cancer cells. In addition, multidrug resistance protein 2 (MRP2) expression is selectively attenuated by HDAC inhibitors, especially SAHA and TSA, in KBV20C cells, whereas MDR1 and BCRP expressions are not affected. This downregulation of MRP2 contributes to increase in paclitaxel-induced G2/M arrest and apoptosis, which might be due to intracellular accumulation of paclitaxel. Collectively, our data provide a molecular rationale for the application of HDAC inhibitors to overcome MDR in cancer cells.

Synthesis of curcumin mimics with multidrug resistance reversal activities

In order to discover novel multidrug resistance (MDR) reversal agents for efficient cancer chemotherapy, the unsymmetrical curcumin mimics with various amide moieties (6-19) were synthesized and evaluated their MDR reversal activities in MDR cell line KBV20C. Among the tested compounds, 13, 16, and 17 showed potent MDR reversal activities by inhibiting drug efflux function of P-glycoprotein in KB20C cells, and almost recovered the cytotoxicity of vincristine and paclitaxel against KBV20C cell to the degree of potency against drug sensitive KB cells.

Histone deacetylase inhibitor apicidin-mediated drug resistance: Involvement of P-glycoprotein

Multidrug resistance (MDR), which is a significant impediment to the success of cancer chemotherapy, is attributable to the overexpression of membrane transport proteins, such as P-glycoprotein (P-gp), resulting in an increased drug efflux. In this study, we show that the histone deacetylase (HDAC) inhibitor apicidin leads to resistance of HeLa cells to paclitaxel through the induction of P-gp expression. Furthermore, apicidin dramatically increases the release of a fluorescent P-gp substrate, rhodamine 123, from cells. In parallel, apicidin resistance to the apoptotic potential of paclitaxel is associated with induction of P-gp expression in HeLa cells, as evidenced by specific inhibition of P-gp function using either the pharmacological inhibitor verapamil or RNA silencing. We also demonstrate the contribution of apicidin-induced functional P-gp expression to drug resistance using KB cells. Failure of P-gp induction by apicidin does not reverse paclitaxel-induced cytotoxicity in the cells. Although HDAC inhibitors are widely appreciated as a new class of anti-tumor agent, our findings clearly demonstrate that apicidin treatment may lead to P-gp-mediated resistance to other anti-tumor agents, suggesting a need for careful design of clinical applications using HDAC inhibitors.

Histone Deacetylase Inhibitor Induction of P-Glycoprotein Transcription Requires Both Histone Deacetylase 1 Dissociation and Recruitment of CAAT/Enhancer Binding Protein β and pCAF to the Promoter Region

Although histone deacetylase (HDAC) inhibitors are appreciated as a promising class of anticancer drugs, recent reports show that P-glycoprotein (P-gp) is induced by HDAC inhibitor treatment in cancer cells, resulting in multidrug resistance of cancer cells to other chemotherapeutic agents. In this study, we investigated the molecular mechanism of HDAC inhibitor induction of P-gp expression. HDAC inhibitor treatment causes cell type–specific induction of P-gp expression without changes in the CpG methylation status of the promoter region. In addition, our data show that HDAC inhibitor does not alter the DNA binding activity of Sp1 but facilitates both the recruitment of a coactivator complex that includes CAAT/enhancer binding protein β and pCAF and the dissociation of the repressive complex, HDAC1, to the Sp1 binding region. Subsequently, the hyperacetylated histone H3 becomes enriched in the promoter region, leading to RNA polymerase II recruitment to activate P-gp gene transcription. Furthermore, specific down-regulation of HDAC1, but not HDAC2, by RNA silencing was enough to induce P-gp expression in HeLa cells, strongly supporting the essential role of HDAC1 in HDAC inhibitor induction of P-gp. Concomitantly, cell type–specific induction of P-gp expression seems to be dependent on phosphatidylinositol 3-kinase activity. Taken together, our findings show that HDAC inhibitor treatment leads to an increase in P-gp expression through dynamic changes in chromatin structure and transcription factor association within the promoter region. (Mol Cancer Res 2009;7(5):735–44)

Anticarcinogenic Effects of Products of Heat-Processed Ginsenoside Re, a Major Constituent of Ginseng Berry, on Human Gastric Cancer Cells

Ginsenoside Re is a triol type triterpene glycoside and is abundantly present in ginseng berry. In the present study, we verified that ginsenoside Re can be transformed into less-polar ginsenosides, namely, Rg2, Rg6, and F4, by heat-processing. The products of heat-processed ginsenoside Re inhibited phosphorylation of CDK2 at Thr160 by upregulation of p21 level, resulting in S phase arrest. The products of heat-processed ginsenoside Re also activated caspase-8, caspase-9, and caspase-3, followed by cleavage of PARP, a substrate of caspase-3, in a dose-dependent manner. Concurrently, alteration of mitochondrial factors such as Bcl-2 and Bax was also observed. Moreover, pretreatment with Z-VAD-fmk abrogated caspase-8, -9, and -3 activations by the products of heat-processed ginsenoside Re. We further confirmed that the anticancer effects of the products of heat-processed ginsenoside Re in AGS cells are mainly mediated via generation of less-polar ginsenosides Rg6 and F4.

Beneficial effects of fermented black ginseng and its ginsenoside 20(S)-Rg3 against cisplatin-induced nephrotoxicity in LLC-PK1 cells

Background Nephrotoxicity is a common side effect of medications. Panax ginseng is one of the best-known herbal medicines, and its individual constituents enhance renal function. Identification of its efficacy and mechanisms of action against drug-induced nephrotoxicity, as well as the specific constituents mediating this effect, have recently emerged as an interesting research area focusing on the kidney protective efficacy of P. ginseng. Methods The present study investigated the kidney protective effect of fermented black ginseng (FBG) and its active component ginsenoside 20(S)-Rg3 against cisplatin (chemotherapy drug)-induced damage in pig kidney (LLC-PK1) cells. It focused on assessing the role of mitogen-activated protein kinases as important mechanistic elements in kidney protection. Results The reduced cell viability induced by cisplatin was significantly recovered with FBG extract and ginsenoside 20(S)-Rg3 dose-dependently. The cisplatin-induced elevated protein levels of phosphorylated c-Jun N-terminal kinase (JNK), p53, and cleaved caspase-3 were decreased after cotreatment with FBG extract or ginsenoside 20(S)-Rg3. The elevated percentage of apoptotic LLC-PK1 cells induced by cisplatin treatment was significantly abrogated by cotreatment with FBG and the ginsenoside 20(S)-Rg3. Conclusion FBG and its major ginsenoside 20(S)-Rg3, ameliorated cisplatin-induced nephrotoxicity in LLC-PK1 cells by blocking the JNK–p53–caspase-3 signaling cascade.