演題抄録

FACO International Workshop

開催概要
開催回
第53回・2015年・京都
 

Ubiquitin ligase inhibitor is an effective therapy in hypoxic colorectal cancer cells

演題番号 : FWS3-4

[筆頭演者]
Gombodorj Navchaa:1,4 
[共同演者]
Yoshiyama Shinji:2、Rokudai Susumu:3、Nishiyama Masahiko:3、Nakano Takashi:1,5

1:Radiation Oncology, Gunma University Graduate School of Medicine、2:Integrated Oncology Research, Gunma University Initiative for Advanced Research、3:Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine、4:Radiation Oncology, National Cancer Center of Mongolia、5:Gunma University Heavy Ion Medical Center

 

Background: We previously generated the Ubiquitin Ligase Inhibitor (UBE2Si) compound targeted to ubiquitin ligase complex, which accumulates HIF-1 and activates its downstream target. In this study, we expectantly investigate our new drug candidate UBE2Si to overcome drug and radioresistance induced by hypoxia. For the purpose, we clarify the molecular mechanisms of 1) New drug candidate effect under hypoxia; 2) Irradiation effect under hypoxia; 3) Combination effect between irradiation and our new drug candidate for hypoxia.

Methods: Our in vitro analysis were carried out in 10 Colorectal cancer (CRC) cell lines, then were selected HCT116 and SW480 as representatives a most sensitive and resistant for irradiation. We searched the new drug candidate alone and a combination with irradiation by determining IC50 for each drug. Cytotoxicity was conducted by using a Cell Counting Kit-8 (CCK-8). Western blot analysis of HIF-1α and NF-kB were performed. Moreover, the effect of UBE2Si in vivo was investigated in CRC xenograft BALB/c nu/nu mice models.

Results: In Hypoxia (O2 1%), the IC50 values of common anti-cancer drugs CPT-11, L-OHP, 5FU and CDDP did not work sufficient effectively and increased in several folds (1.32-9.7) in HCT and SW480 CRC cells. But IC50 value of UBE2Si in radiosensitive HCT116 slightly less increased (1.26 fold) from 2.8±0.2μM to 3.53±0.08μM and in radioresistant SW480 conversely decreased (0.94 fold) from 1.31±0.14μM to 1.23±0.19μM respectively. In addition to in vitro results, it significantly suppressed the growth of HCT116 and SW480 xenograft in nude mice (p<0.05).

Conclusion: Our new drug candidate developed for suppressing HIF-1 activation and transcription targets of HIF-1 works specifically to hypoxic cancer cells. Our data suggested that our drug candidate UBE2Si development might be connected to more effective method of cancer therapy.

キーワード

臓器別:大腸・小腸

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