• BMB Reports
• /
• 제31권3호
• /
• pp.269-273
• /
• 1998

The objective of this study was to evaluate the reversal of multi drug resistance of human cell lines by specific inhibitors of ${\alpha}-glycosidase$ and mannosidases that had been reported to be involved in N-linked oligosaccharide processing of glycoproteins. N-methyldeoxynojirimycin, I-deoxynojirimycin, and castanospermine, which were known to be potent inhibitors of both ${\alpha}-glycosidase$ I and II, showed no activity against the multidrug resistant phenotype of the cell lines of SNU1DOX, KB-V1, and MCF-7/ADR. In contrast, I-deoxymannojirimycin, an inhibitor of mannosidase I, resulted in a slight reversal for the vinblastine resistance of the KB-V1 cell line, but did not show any activity toward the other cell lines. Parallel experiments with tunicamycin, an inhibitor of N-linked glycosylation, also resulted in no significant changes in multidrug resistant (MDR) phenotype of the cell lines tested in this work. These observations suggest that the unglycosylation of P-glycoprotein associated with the inhibitor treatments might not be correlated with the reversal of multidrug resistance of the cell lines tested in this study.

• Biomolecules & Therapeutics
• /
• 제3권2호
• /
• pp.116-121
• /
• 1995

Some multidrug resistance inhibitors have been known to be influenced by the serum concentration. In this study, effect of serum concentration on inhibition of nucleoside transport by BIBW22, a new multidrug resistance inhibitor derived from dipyridamole (DPM), was studied. When 5% or 100% (v/v) of fetal bovine serum (FBS) was contained in the culture, DPM dose for which nucleoside transport was inhibited by 50% (lD$_{50}$) was 0.42 $\mu$M or 1.17 $\mu$M, respectively. BIBW22 also showed the same trend as DPM did in response to increase of FBS concentration. However, ID$_{50}$ value for DPM in the absence or presence of human plasma was 0.007 $\mu$M or 1.02 $\mu$M respectively showing 145 times increase of ID$_{50}$ value. ID$_{50}$ value for BIBW22 in the presence of human plasma was 0.028 $\mu$M showing only 5 times increase in ID$_{50}$ value. This result suggests that potency of BIBW22 was much less affected by the plasma concentration and BIBW22 could be a good candidate for a clinical use in multidrug resistance treatment.treatment.

• Journal of Microbiology and Biotechnology
• /
• 제26권12호
• /
• pp.2043-2050
• /
• 2016

Exploring novel antibiotics is necessary for multidrug-resistant pathogenic bacteria. Because the probiotics in soybean food have antimicrobial activities, we investigated their effects on multidrug-resistant Acinetobacter baumannii. Nineteen multidrug-resistant A. baumannii strains were clinically isolated as an experimental group and 11 multidrug-sensitive strains as controls. The growth rates of all bacteria were determined by using the analysis for xCELLigence Real-Time Cell. The combination of antibiotics showed synergistic effects on the strains in the control group but no effect on the strains in the experimental group. Efflux pump gene adeS was absent in all the strains from the control group, whereas it exists in all the strains from the experimental group. Furthermore, all the strains lost multidrug resistance when an adeS inhibitor was used. One strain of probiotics isolated from soybean food showed high antimicrobial activity for multidrug-resistant A. baumannii. The isolated strain belongs to Bacillus subtilis according to 16S RNA analysis. Furthermore, E. coli showed multidrug resistance when it was transformed with the adeS gene from A. baumannii whereas the resistant bacteria could be inhibited completely by isolated Bacillus subtilis. Thus, probiotics from soybean food provide potential antibiotics against multidrug-resistant pathogenic bacteria.

• Archives of Pharmacal Research
• /
• 제21권3호
• /
• pp.344-347
• /
• 1998

To overcome multidrug resistance (MDR) in cancer chemotherapy, we prepared various plant extracts and searched for a component which is effective for inhibition of MDR. MDR inhibition activity was determined by measuring cytotoxicity to MDR cells using multidrug resistant human fibrocarcinoma KB V20C, which is resistant to 20 nM vincristine and expresses high level of mdr1 gene. Of various plant extracts, the MeOH extract of the root of Aconitum pseudo-laeve var. erectum was found to have potent inhibitory activity on MDR. The bioassayguided fractionation of the MeOH extract of the plant led to the isolation of an alkaloid, lycaconitine, as an active principle. And the $IC_{50}$ of lycaconitne for KB V20C cells was $74\mu{g}$/ml.

• Biomolecules & Therapeutics
• /
• 제20권4호
• /
• pp.393-398
• /
• 2012

Recently, we reported that defective autophagy may contribute to the inhibition of the growth in response to PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine), a selective SFK inhibitor, in multidrug-resistant v-Ha-ras-transformed NIH 3T3 cells (Ras-NIH 3T3/Mdr). In this study, we demonstrated that PP2 induces LC3 conversion via a mechanism that is uncoupled from autophagy and increases apoptosis in Ras-NIH 3T3/Mdr cells. PP2 preferentially induced autophagy in Ras-NIH 3T3 cells rather than in Ras-NIH 3T3/Mdr cells as determined by LC3-I to LC3-II conversion and GFP-LC3 fluorescence microscopy. Beclin 1 knockdown experiments showed that, regardless of drug resistance, PP2 induces autophagy via a Beclin 1-dependent mechanism. PP2 induced a conformational change in Beclin 1, resulting in the enhancement of the pro-autophagic activity of Beclin 1, in Ras-NIH 3T3 cells. Further, PI3K inhibition induced by wortmannin caused a significant increase in apoptosis in Ras-NIH 3T3 cells, as demonstrated by flow cytometric analysis of Annexin V staining, implying that autophagy inhibition through PI3K increases apoptosis in response to PP2 in Ras-NIH 3T3 cells. However, despite the fact that wortmannin abrogates PP2-induced GFP-LC3 punctae formation, some LC3 conversion remains in Ras-NIH 3T3/Mdr cells, suggesting that LC3 conversion may occur in an autophagy-independent manner. Taken together, these results suggest that PP2 induces LC3 conversion independent of PI3K, concomitant with the uncoupling of LC3 conversion from autophagy, in multidrug-resistant cells.

• Asian Pacific Journal of Cancer Prevention
• /
• 제17권1호
• /
• pp.51-55
• /
• 2016

Phytochemical investigation of Pistacia integerrima has highlighted isolation of two known compounds naringenin (1) and dihydrokaempferol (2). A crude extract and these isolated compounds were here evaluated for their effects on reversion of multidrug resistance (MDR) mediated by P-glycoprotein (P-gp). The multidrug resistance P-glycoprotein is a target for chemotherapeutic drugs from cancer cells. In the present study rhodamine-123 exclusion screening test on human mdr1 gene transfected mouse gene transfected L5178 and L5178Y mouse T-cell lymphoma cells showed excellent MDR reversing effects in a dose dependent manner. In-silico molecular docking investigations demonstrated a common binding site for Rhodamine123, and compounds naringenin and dihydrokaempferol. Our results showed that the relative docking energies estimated by docking softwares were in satisfactory correlation with the experimental activities. Preliminary interaction profile of P-gp docked complexes were also analysed in order to understand the nature of binding modes of these compounds. Our computational investigation suggested that the compounds interactions with the hydrophobic pocket of P-gp are mainly related to the inhibitory activity. Moreover this study s a platform for the discovery of novel natural compounds from herbal origin, as inhibitor molecules against the P-glycoprotein for the treatment of cancer.

• 생명과학회지
• /
• 제28권7호
• /
• pp.778-785
• /
• 2018

오토파지(Autophagy, 자가포식)는 복합적인 신호과정으로, 암세포의 증식 억제 및 항암제에 대한 내성 획득의 상반적인 조절에도 관여한다. 오토파지의 암 억제 효과는 아팝토시스(apoptosis)와 상호협력으로 오토파지성세포 사멸의 유도에 기인된다. 본 연구에서는 NSAID 계열의 다기능 약물인 celecoxib (CCB)이 아팝토시스 및 오토파지의 복합적인 유도로, 항암제 다제내성(multidrug resistant, MDR) 암세포의 Hsp90 molecular chaperone inhibitor인 17-allylamino-17-demethoxygeldanamycin (17-AAG)에 대한 감수성을 증가시키는 활성이 있음을 밝혔다. 17-AAG 처리에 의한 항암제 다제내성 암세포의 변이형p53 분해 및 caspase-3 활성은 CCB 처리로 촉진되었다. MCF7-MDR세포에서 Z-DEVD-FMK 처리에 의한 caspase-3-매개의 아팝토시스 경로 차단은 CCB 유도의 세포 사멸을 완전히 차단시키지 못함을 알 수 있었으며, 또한 17-AAG과 CCB 병합 처리에 의한 오토파지 활성화는 Z-DEVD-FMK에 의해 방해되지 않는 것을 알 수 있었다. 본 연구의 결과를 토대로, CCB의 오토파지 유도 활성은 항암제 다제내성 암의 Hsp90 inhibitor에 대한 감수성 증가를 위한 약물 개발에, CCB가 효과적인 병용 약물로서 제안 될 수 있다.

• Biomolecules & Therapeutics
• /
• 제21권2호
• /
• pp.114-120
• /
• 2013

Most patients with mutant B-Raf melanomas respond to inhibitors of oncogenic B-Raf but resistance eventually emerges. To better understand the mechanisms that determine the long-term responses of mutant B-Raf melanoma cells to B-Raf inhibitor, we used chronic selection to establish B-Raf (V600E) melanoma clones with acquired resistance to the new oncogenic B-Raf inhibitor UI-152. Whereas the parental A375P cells were highly sensitive to UI-152 ($IC_{50}$ < $0.5{\mu}M$), the resistant sub-line (A375P/Mdr) displayed strong resistance to UI-152 ($IC_{50}$ < $20{\mu}M$). Immunofluorescence analysis indicated the absence of an increase in the levels of P-glycoprotein multidrug resistance (MDR) transporter in A375P/Mdr cells, suggesting that resistance was not attributable to P-glycoprotein overexpression. In UI-152-sensitive A375P cells, the anti-proliferative activity of UI-152 appeared to be due to cell-cycle arrest at $G_0/G_1$ with the induction of apoptosis. However, we found that A375P/Mdr cells were resistant to the apoptosis induced by UI-152. Interestingly, UI-152 preferentially induced autophagy in A375P/Mdr cells but not in A375P cells, as determined by GFP-LC3 puncta/cell counts. Further, autophagy inhibition with 3-methyladenine (3-MA) partially augmented growth inhibition of A375P/Mdr cells by UI-152, which implies that a high level of autophagy may protect UI-152-treated cells from undergoing growth inhibition. Together, our data implicate high rates of autophagy as a key mechanism of acquired resistance to the oncogenic B-Raf inhibitor, in support of clinical studies in which combination therapy with autophagy targeted drugs is being designed to overcome resistance.

• Bulletin of the Korean Chemical Society
• /
• 제32권12호
• /
• pp.4444-4446
• /
• 2011

• Biomolecules & Therapeutics
• /
• 제5권3호
• /
• pp.265-271
• /
• 1997

Since the advent of chemotherapy, certain types of cancer have been particularly resistant to chemotherapeutic treatment. One of the most well-studied types of resistance is resistance to multiple struc-turally dissimialr hydrophobic chemotherapeutic agents, or multidrug resistance (MDR). We found that MDR cells (KBV20C, KB7D) being highly resistant to colchicine, etoposide, and vincristine were found to have very low level of putrescine and low level of spermidine than the drug sensitive parental cells (KB) but they had almost same level of spermine as the drug sensitive cells. Although both MDR and drug sensitive cells had almost same rate of polyamine uptake, MDR cells were much more sensitive to an inhibitor of polyamine synthesis, methylglyoxal-bis guanylhydrazone (MGBG), suggesting that MDR cells might be defective in polyamine synthesis. These results also suggest that HGBG can be used for treatment of MDR in vivo.