열 충격 단백질인 heat shock protein 90 (Hsp90)은 종양 형성 과정에서 중요한 역할을 하고 있으며, 이에 따라 1세대 및 2세대 Hsp90저해제들이 개발되어, 다양한 암에서의 항암 효과가 보고되어 있다. 2세대 Hsp90저해제로 개발된 BIIB021는 1세대 Hsp90저해제인 17-allylamino-17-demethoxygeldanamycin (17-AAG)에 내성을 나타내는 항암제 다제내성(MDR) 암세포에 감수성을 가진다고 알려져 있지만, 본 연구에서 BIIB021에 내성인 MDR세포로서, MCF7-MDR 및 HeyA8-MDR세포가 해당됨을 밝혔다. BIIB021 감수성을 증강시키는 물질로 비스테로이드성 항염증약물(NSAID)인 dimethyl-celecoxib (DMC)의 BIIB021의 효과 증강 활성을 BIIB021-내성 및 -감수성 MDR 세포에서 확인하였다. MDR세포에 NSAID와 BIIB021의 병합 처리한 경우, NSAID의 자가분해(autophagy) 유도 활성에 의해 MDR세포에서 과잉 발현하는 변이형 mutant p53 (mutp53)을 분해할 뿐만 아니라 BIIB021 처리로 유도되는 Hsp70 발현을 억제하므로써, 암세포의 BIIB021 내성을 극복할 수 있는 활성을 나타내었다. 또한 NSAID 물질인 sulindac sulfate 및 FDA 승인 약물인 niclosamide 도 자가분해 유도 활성으로 Hsp90의 타켓 단백질 인 mutp53 및 c-Myc의 분해를 유도하므로서, 17-AAG 효과를 증강시켰다. 그러므로 본 연구에서는 새로운 BIIB021에 대한 효과 증강 및 내성 극복 물질로서, NSAIDs 및 niclosamide를 발굴하였으며, 이들 물질의 자가분해 경로 활성화에 의하여, BIIB021 효과를 극대화 시킴을 밝혔다.
열 충격 단백질인 heat shock protein 90 (Hsp90)은 종양 형성 과정에서 중요한 역할을 하고 있으며, 이에 따라 1세대 및 2세대 Hsp90저해제들이 개발되어, 다양한 암에서의 항암 효과가 보고되어 있다. 2세대 Hsp90저해제로 개발된 BIIB021는 1세대 Hsp90저해제인 17-allylamino-17-demethoxygeldanamycin (17-AAG)에 내성을 나타내는 항암제 다제내성(MDR) 암세포에 감수성을 가진다고 알려져 있지만, 본 연구에서 BIIB021에 내성인 MDR세포로서, MCF7-MDR 및 HeyA8-MDR세포가 해당됨을 밝혔다. BIIB021 감수성을 증강시키는 물질로 비스테로이드성 항염증약물(NSAID)인 dimethyl-celecoxib (DMC)의 BIIB021의 효과 증강 활성을 BIIB021-내성 및 -감수성 MDR 세포에서 확인하였다. MDR세포에 NSAID와 BIIB021의 병합 처리한 경우, NSAID의 자가분해(autophagy) 유도 활성에 의해 MDR세포에서 과잉 발현하는 변이형 mutant p53 (mutp53)을 분해할 뿐만 아니라 BIIB021 처리로 유도되는 Hsp70 발현을 억제하므로써, 암세포의 BIIB021 내성을 극복할 수 있는 활성을 나타내었다. 또한 NSAID 물질인 sulindac sulfate 및 FDA 승인 약물인 niclosamide 도 자가분해 유도 활성으로 Hsp90의 타켓 단백질 인 mutp53 및 c-Myc의 분해를 유도하므로서, 17-AAG 효과를 증강시켰다. 그러므로 본 연구에서는 새로운 BIIB021에 대한 효과 증강 및 내성 극복 물질로서, NSAIDs 및 niclosamide를 발굴하였으며, 이들 물질의 자가분해 경로 활성화에 의하여, BIIB021 효과를 극대화 시킴을 밝혔다.
The critical role of heat shock protein 90 (Hsp90) in tumorigenesis led to the development of several first- and second-generation Hsp90 inhibitors, which have demonstrated promising responses in cancers. In this study, we found second-generation Hsp90 inhibitor BIIB021-resistant multidrug-resistant...
The critical role of heat shock protein 90 (Hsp90) in tumorigenesis led to the development of several first- and second-generation Hsp90 inhibitors, which have demonstrated promising responses in cancers. In this study, we found second-generation Hsp90 inhibitor BIIB021-resistant multidrug-resistant (MDR) human cancer cells, although BIIB021 was shown to be active in first-generation Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG)-resistant MDR cells. MCF7-MDR and HeyA8- MDR cells were more resistant to BIIB021 than their parental counterparts, indicating that BIIB021 cannot be applicable to all cancer cells expressing MDR proteins. We revealed that dimethyl-celecoxib (DMC), one of the non-steroidal anti-inflammatory drugs (NSAIDs), potentiated cytotoxicity of BIIB021 against both BIIB021-resistant and BIIB021-sensitive MDR cells. The effectiveness of NSAIDs involving celecoxib and DMC in combination with BIIB021 led to the autophagic degradation/down-regulation of mutant p53 (mutp53) that overexpressed MDR cells and the suppression of Hsp70 induction. This resulted in sensitization of MDR cells to BIIB021. Moreover, autophagy induction by sulindac sulfide, another type of NSAID, and niclosamide, an FDA-approved anthelmintic drug, potentiated 17-AAG-mediated autophagic degradation/down-regulation of mutp53 and c-Myc, client proteins of Hsp90. Therefore, our results suggest that NSAIDs and niclosamide positively enhance the anticancer activity of Hsp90 inhibitors through an autophagic pathway. They may also be new candidates for sensitizing MDR cells to Hsp90 inhibitors.
The critical role of heat shock protein 90 (Hsp90) in tumorigenesis led to the development of several first- and second-generation Hsp90 inhibitors, which have demonstrated promising responses in cancers. In this study, we found second-generation Hsp90 inhibitor BIIB021-resistant multidrug-resistant (MDR) human cancer cells, although BIIB021 was shown to be active in first-generation Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG)-resistant MDR cells. MCF7-MDR and HeyA8- MDR cells were more resistant to BIIB021 than their parental counterparts, indicating that BIIB021 cannot be applicable to all cancer cells expressing MDR proteins. We revealed that dimethyl-celecoxib (DMC), one of the non-steroidal anti-inflammatory drugs (NSAIDs), potentiated cytotoxicity of BIIB021 against both BIIB021-resistant and BIIB021-sensitive MDR cells. The effectiveness of NSAIDs involving celecoxib and DMC in combination with BIIB021 led to the autophagic degradation/down-regulation of mutant p53 (mutp53) that overexpressed MDR cells and the suppression of Hsp70 induction. This resulted in sensitization of MDR cells to BIIB021. Moreover, autophagy induction by sulindac sulfide, another type of NSAID, and niclosamide, an FDA-approved anthelmintic drug, potentiated 17-AAG-mediated autophagic degradation/down-regulation of mutp53 and c-Myc, client proteins of Hsp90. Therefore, our results suggest that NSAIDs and niclosamide positively enhance the anticancer activity of Hsp90 inhibitors through an autophagic pathway. They may also be new candidates for sensitizing MDR cells to Hsp90 inhibitors.
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가설 설정
Since the cytotoxicity of BIIB021 in MDR cells showed no correlation with P-gp level in only two tested MDR variants [19], it is necessary to test various MDR cells derived from different types of tumors. In this study, we determined whether BIIB021 could be active against various MDR cells derived from different types of tumors, and also developed new sensitizers that enhance cytotoxicity of Hsp90 inhibitors and thus reverse Hsp90 inhibitor resistance of MDR cells.
대상 데이터
Louis, MO, USA). BIIB021 (Selleckchem, Houston, TX, USA), niclosamide and sulindac sulfide (Sigma-Aldrich, St. Louis, MO, USA) were used in this study.
데이터처리
A Student’s t-test was used to calculate the statistical significance of the experimental data and the level of significance was set as *p<0.05, **p<0.01 and ***p<0.001.
이론/모형
Cell proliferation was measured by counting viable cells by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric dye-reduction method. Exponentially growing cells (1- or 2×104 cells/well) were plated in a 96-well plate and incubated in growth medium treated with the indicated concentration of BIIB021 and DMC (or CCB) at 37℃.
성능/효과
The combined effect of BIIB021 and CCB/DMC reduce BIIB021-mediated mutp53 via the induction of autophagy, which might trigger cell death in MDR cells. In addition, our data showed that sulindac sulfide (SS) and niclosamide (NC) had autophagic autophagy-inducing ability, which may contribute to the ability of enhancing BIIB021 sensitivity. Present study showed that non-steroidal anti-inflammatory drugs (NSAIDs) such as CCB, DMC and SS induced autophagy irrespective of their COX selectivity since both DMC and SS are non-selective COX inhibitors but CCB is a cyclooxygenase (COX)-2 selective inhibitor.
In conclusion, we found potentiating effect of NSAIDs on BIIB021 activity in MDR cells, and sensitization of BIIB021-resistant MDR cells to BIIB021 through autophagic degradation of mutp53 and suppression of Hsp70 induction by NSAIDs. In addition, SS and NC possessing autophagy-inducing activity could be new sensitizers of Hsp90 inhibitors including BIIB021.
3). In this experiment, the percentage of cells in both the lower and upper right quadrants of the Annexin/PI analysis was significantly increased by co-treatment with BIIB021 and CCB (or DMC) versus BIIB021 alone, indicating sensitization of MDR cells to BIIB021-induced apoptosis by NSAIDs. These results suggest the possibility that NSAIDs such as DMC and CCB could be candidate sensitizers for BIIB021-resistant MDR cells.
Previous study showed that BIIB021 was relatively independent of MDR1 expression and was active against P-gp expressing cell lines [19]. In this study, we found that BIIB021 cannot be applicable to all cancer cells expressing MDR proteins since MCF7-MDR and HeyA8-MDR cells were more resistant to BIIB021 than their parental counterparts but BIIB021 was sensitive to CEM/VLB100 cells, indicating differential responses of MDR cells to BIIB021. Moreover, we showed that CCB and its derivative DMC that belongs to the NSAIDs could be as new sensitizers of BIIB021 as well as 17-AAG in MDR cells.
DMC is more effective than CCB against down-regulation of mutp53 and suppression of Hsp70 induction in BIIB021-treated cells. These results indicated the possibility that combined effect of BIIB021 and CCB/DMC on the induction of autophagy would reduce BIIB021-mediated mutp53, which triggered apoptosis in CEM/VLB100 cells. These results suggest the possibility that NSAID including CCB and DMC could be a new class of BIIB021 sensitizer through suppression of Hsp70 induction that limits the clinical benefits of Hsp90 inhibitors.
These results indicated the possibility that combined effect of BIIB021 and CCB/DMC on the induction of autophagy would reduce BIIB021-mediated mutp53, which triggered apoptosis in CEM/VLB100 cells. These results suggest the possibility that NSAID including CCB and DMC could be a new class of BIIB021 sensitizer through suppression of Hsp70 induction that limits the clinical benefits of Hsp90 inhibitors.
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