HIF-1alpha: a Valid Therapeutic Target for Tumor Therapy

홍순선,이현승,김규원 대한암학회 2004 Cancer Research and Treatment Vol.36 No.6

Hypoxia plays a major role in the induction of angiogenesis during tumor development. One mechanism by which tumor cells respond to a reduced oxygen level is via the activation of hypoxia-inducible factor-1 (HIF-1).HIF-1 is an oxygen-dependent transcriptional activator that plays crucial roles in the angiogenesis of tumors and mammalian development. HIF-1 consists of a constitutively expressed HIF-1β subunit and the highly regulated HIF-1α subunits. The stability and activity of HIF-1α are regulated by various post-translational modifications, hydroxylation, acetylation, phosphorylation and sumoyaltion.Therefore, HIF-1α interacts with several protein factors including PHD, pVHL, ARD-1, SUMO and p300/ CBP.Under normoxia, the HIF-1α subunit is rapidly degraded via the von Hippel-Lindau tumor suppressor gene product (pVHL)-mediated ubiquitin/proteasome pathway. The association of pVHL and HIF-1α under normoxic conditions is triggered by the hydroxylation of prolines and the acetylation of lysine within a polypeptide segment known as the oxygen-dependent degradation (ODD) domain. On the contrary, under the hypoxia condition, the HIF-1α subunit becomes stable and interacts with coactivators such as p300/CBP to modulate its transcriptional activity. Under hypoxic conditions, HIF-1 eventually acts as a master regulator of numerous hypoxia-inducible genes.The target genes of HIF-1 are especially related to angiogenesis, cell proliferation and survival, and to glucose and iron metabolism. Moreover, it was reported that the activation of HIF-1α is closely associated with a variety of tumors and oncogenic pathways. Hence, the blocking of HIF-1α itself or the blocking of HIF-1α interacting proteins inhibits tumor growth. Based on these findings, HIF-1 can be a prime target for anticancer therapies. Therefore, this review summarizes the molecular mechanism of HIF-1α stability, the biological functions of HIF-1 and its potential applications for cancer therapies.

리포솜 봉입이 로다민 123의 소장 흡수에 미치는 영향

홍순선,이해리,이홍,정석재,김대덕,심창구,Hong, Soon-Sun,Lee, Hae-Ree,Li, Hong,Chung, Suk-Jae,Kim, Dae-Duk,Shim, Chang-Koo 대한약학회 2005 약학회지 Vol.49 No.2

The absorption of a P-gp substrate, rhodamine 123, from a liposomal dosage form was investigated across Caco-2 cell monolayers, rat intestines and rat intestinal Peyer's patches in Ussing chamber, Rhodamine 123 was incorporated into liposomes according to the standard evaporation method, which led to a production of liposomes with a mean diameter of 71.3 nm. The permeability (Papp of rhodamine 123 from a water solution across the monolayer was $2.45{\times}10^{-6}$ cm/s for $A{\leftrightarrow}B$ (apical to basal) and $14.0{\times}10^{-6}$ cm/s for $B{\leftrightarrow}A$ (basal to apical) directions, consistent with the fact that rhodamine 123 is one of the P-gp substrates. The transport of rhodamine 123 from the liposomal dosage form was much lower for both directions compared to the solution of rhodamine 123. The transport of rhodamine 123 across the rat intestine was also significantly decreased for both directions, I.e., influx and efflux, by the liposomal incorporation of the compound. The transport of rhodamine 123 across the Peyer's patch was substantially reduced by liposomal incorporation. No difference was found in the transport between the Peyer's patch and non-Peyer's patch. These observations suggest that the contribution of transport via Peyer's patches in the uptake of liposomes may be minimal, especially for rapidly absorbed compounds like rhodamine 123. Therefore, the increased absorption of P-gp substrates does not appear to be feasible by incorporating the compounds in liposomes, due to negligible involvement of Peyer's patches in the uptake of particulate dosage forms like liposomes. Liposomes may rather represent a sustained release dosage form of incorporated compounds.

Caco-2 세포 단층막 투과 실험시 교반이 약물의 투과계수에 미치는 영향

홍순선,유호정,이홍,정석재,김대덕,심창구 한국약제학회 2005 Journal of Pharmaceutical Investigation Vol.35 No.2

The unstirred water layer (UWL), which has been known to exist in the boundary of the intestinal lumen and intestinal wall, often behaves as an absorption barrier especially for lipophilic drugs. The intestinal absorption of drugs is often characterized using Caco-2 cell monolayers grown on Transwell polycarbonate membranes. The permeability (Pare) of drugs across the cell monolayer might be influenced by the agitation of the donor compartment, since the width of UWL on the surface of the cell monolayer would be reduced by the agitation. In this study, the effect of agitation of the donor compartment with 60 rpm on the permeability was measured for 12 drugs with a wide range of lipophilicity and permeability. The of mannitol, tributylmethyl ammonium, cimetidine, ranitidine, hydrocortisone, benzylpenicillin and loxoprofen was not influenced by the agitation, while the P_(app) of theophylline, propranolol, YH439, phenylpropanolarnine and testosterone was increased by the agitation. There was a significant correlation between the increase of P_(app) by agitation and the lipophilicity for the compounds having P_(app) > 2 x 10^(-5) cm/sec. No correlation was observed for the difference in P_(app) by agitation and the molecular weight, or lipophilicity of the drugs. Therefore, the agitation rate of the donor compartment in the Caco-2 cell monolayer study should be carefully controlled in order to estimate Pap, reproducibly especially for iipophilic drugs.

Advanced Formulation and Pharmacological Activity of Hydrogel of the Titrated Extract of C. Asiatica

홍순선,Jong-Ho Kim,Hong Li,심창구 대한약학회 2005 Archives of Pharmacal Research Vol.28 No.4

Titrated extract of Centella asiatica (TECA) contains three principal ingredients, asiaticoside (AS), asiatic acid (AA), and madecassic acid (MA). These components are known to be clinically effective on systemic scleroderma, abnormal scar formation, and keloids. However, one problem associated with administration of TECA is its low solubility in aqueous as well as oil medium. In this study, various nonionic surfactants and bile salts as anionic surfactant were tested and screened for solubilizing TECA with a view to developing topical hydrogel type of ointment which is stable physicochemically, and has better pharmacological effects. When TECA was incorporated into various nonionic surfactant systems, labrasol had the most potent capacity for solubilizing TECA. In cases of bile salt systems, Na-deoxycholate (Na-DOC) had foremost solubilizing capacity, even more than labrasol. In differential scanning calorimetric study, the peaks of AA, MA, AS and Na-DOC disappeared at the coprecipitate of 1% TECA and 1 % Na-DOC, suggesting the optimum condition of Na-DOC for solubilizing TECA. When the physicochemical stability of hydrogel containing this mixture was assessed, it was stable at room temperature for at least one month. Pharmacologically it significantly decreased the size of wound area at the 9th day when applied to the wound area of rat dorsal skin. Taken together, solubility of TECA was dramatically improved by using nonionic and anionic surfactant systems, and Na-DOC was found to be the most effective solubilizer of TECA in formulating a TECA-containing hydrogel typed ointment. Moreover this gel was considered to be applicable to clinical use for wound healing effect.

Altered Pharmacokinetics and Hepatic Uptake of TBuMA in Ethynylestradio-Induced Cholestasis

홍순선,최종문,진효언,심창구 대한약학회 2006 Archives of Pharmacal Research Vol.29 No.4

The objective of this study was to examine the pharmacokinetics of organic cations in intrahepatic cholestatic rats. A pretreatment with 17α-ethynylestradiol was used to induce intrahepatic cholestasis, and tributylmethylammonium (TBuMA) was used as a representative model organic cation. When [3H]TBuMA was intravenously administered, the AUC value for TBuMA was significantly increased by 79% in cholestasis, and its total systemic clearance was consequently decreased by 46%. In addition, the in vivo hepatic uptake clearance of TBuMA from the plasma to the liver was decreased by 50% in cholestasis. The concentration of bile salts in plasma was increased by 2.1 fold in cholestatic rats. Since TBuMA forms ion-pair complexes with anionic components such as bile salts, the decreased hepatic uptake of TBuMA in cholestasis may be due to a change in endogenous components, e.g., bile salts in the plasma. In isolated normal hepatocytes, the uptake clearance for TBuMA in the presence of cholestatic plasma was decreased by 20% compared with normal plasma. Therefore, we conclude that the inhibition of the hepatic uptake process by the cholestasis may be in part due to the increased formation of ion-pair complexes of TBuMA with bile salts in the plasma.

Effect of a New Hepatoprotective Agent, YH-439, on the Hepatobiliary Transport of Organic Cations (OCs): Selective Inhibition of Sinusoidal OCs Uptake without Influencing Glucose Uptake and Canalicular OCs Excretion

홍순선,Hong Li,최민구,정석재,심창구 대한약학회 2005 Archives of Pharmacal Research Vol.28 No.3

The effect of a new hepatoprotective agent, YH-439, on the hepatobiliary transport of a model organic cation (OC), TBuMA (tributylmethylammonium), was investigated. The area under the plasma concentration-time curve (AUC) from time zero to 4 h following iv administration of TBuMA (6.6 µmol/kg) was increased significantly when YH-439 in corn oil (300 mg/kg) was orally administered to rats 24 h prior to the experiment. Nevertheless, the cumulative biliary excretion of TBuMA remained unchanged. As a consequence, the apparent biliary clearance (CLb) of TBuMA was decreased significantly as a result of YH-439 pretreatment, consistent with the fact that the in vivo excretion clearance of TBuMA across the canalicular membrane (CLexc) was not changed by the pretreatment. The in vitro uptake of TBuMA into isolated hepatocytes was decreased by one half by the pretreatment, owing to a decrease in the apparent Vmax and CLlinear, but the Km for the process remained constant. Most interestingly, however, the sinusoidal uptake of glucose, a nutrient, into hepatocytes was not influenced by the pretreatment, suggesting the YH-439 pretreatment specifically impaired the sinusoidal uptake of OCs. Thus, the OC-specific inhibition of hepatic uptake, without influencing the uptake of glucose, a nutrient, appeared to be associated with the hepatoprotective activity of YH-439.

Mechanism of Intestinal Transport of an Organic Cation, Tributylmethylammonium in Caco-2 Cell Monolayers

홍순선,Sang-Cherl Moon,심창구 대한약학회 2006 Archives of Pharmacal Research Vol.29 No.4

Many quaternary ammonium salts are incompletely absorbed after their oral administration and may also be actively secreted into the intestine. However, the underlying mechanism(s) that control the transport of these cations across the intestinal epithelium is not well understood. In this study, the mechanism of absorption of quaternary ammonium salts was investigated using Caco-2 cell monolayers, a human colon carcinoma cell line. Tributylmethylammonium (TBuMA) was used as a model quaternary ammonium salts. When TBuMA was administrated at a dose of 13.3 ìmole/kg via iv and oral routes, the AUC values were 783.7 ± 43.6 and 249.1±28.0 µmole·min/L for iv and oral administration, indicating a lower oral bioavailability of TBuMA (35.6%). The apparent permeability across Caco-2 monolayers from the basal to the apical side was 1.3 times (p<0.05) greater than that from the apical to the basal side, indicating a net secretion of TBuMA in the intestine. This secretion appeared to be responsible for the low oral bioavailability of the compound, probably mediated by p-gp (p-glycoprotein) located in the apical membrane. In addition, the uptake of TBuMA by the apical membrane showed a Na+ dependency. Thus, TBuMA appears to absorbed via a Na+ dependent carrier and is then secreted via p-gp related carriers.

CCl4 급성간장해는 유기양이온의 유동층막을 선택적으로 손상시킨다

홍순선(S . S . Hong),정석재(S . J . Chung),이민화(M . H . Lee),심창구(C . K . Shim) 한국약제학회 1999 한국약제학회 총회 및 학술대회 요지집 Vol.- No.29

N/A N/A

7. CCl4 가 양이온 약물의 간 - 담즙 수송에 미치는 영향

홍순선(Soon Sun Hong),정석재(Suk Jae Chung),이민화(Min Hwa Lee),심창구(Chang Koo Shim) 한국약제학회 1997 한국약제학회 총회 및 학술대회 요지집 Vol.- No.27

N/A

CCl4 간장해시 양이온 약물의 hepatic uptake 감소

홍순선(S . S . Hong),정석재(S . J . Chung),이민화(M . H . Lee),심창구(C . K . Shim) 한국약제학회 1998 한국약제학회 총회 및 학술대회 요지집 Vol.- No.28

N/A N/A