Evaluation of the possibility of combining YM155 with Amiodarone for the future YM155-based anticancer clinical trials

  • 蔡 如雅

Student thesis: Master's Thesis


Survivin an inhibitor-of-apoptosis protein is highly expressed in vast majority of tumors and contributes to their resistance to apoptotic stimuli and chemotherapies Survivin expression also correlates with an advanced carcinoma and poor survival rate in several cancers Despite survivin is an attractive target for anticancer treatment there are few selective inhibitors available due to its “semi- druggable” properties In the past ten years only one small molecule survivin inhibitor YM155 shows favorable human pharmacokinetic properties and has reached phase II clinical trial However phase II clinical studies of YM155 monotherapy and YM155-combination therapy show disappointing results Because YM155 is a substrate of the multi-drug resistant protein MDR1 which is frequently overexpressed in patients with advanced cancer; therefore in this study we aimed to investigate whether combining YM155 with a clinically used drug that exhibits MDR1 inhibitory property can bring better outcome for the YM155 survivin-targeted therapy in the future Amiodarone is a clinically used antiarrhythmic drug for the prevention of atrial fibrillation and recent studies reported that it can induce autophagy to inhibit tumor progression Amiodarone is also known to exhibit MDR1 inhibitory effects In this study human cervical KB carcinoma cells and KB-derived MDR1-expressing multi-drug resistant KB-TAX50 and KB-VIN10 carcinoma cells were used as models MDR1 activity assay confirmed that amiodarone within the clinically used concentration range could inhibit the activity of MDR1 in KB-TAX50 and KB-VIN10 cells Importantly results of the MTT cell viability assay and LDH cytotoxicity assay revealed that co-treatment of 2 ?M amiodarone significantly re-sensitized KB-TAX50 and KB-VIN10 to YM155 Western blot analysis showed that the amiodarone-YM155 combination treatment increased the expression of the apoptotic markers such as caspase-3 and PARP cleavage indicating the induction of apoptosis in the treated MDR1-expressing cancer cells Our previous study revealed that YM155 induces cancer cell death in part through induction of autophagy and autophagy-dependent DNA damage Here YM155-amiodarone combination treatment showed an enhanced formation of AVOs and reduced expression of p62/SQSTM1 which is an autophagy flux marker indicating that the combination treatment up-regulates autophagy in KB-TAX50 and KB-VIN10 cells Interestingly PCR analysis revealed that the combination treatment synergistically decreased the expression of MDR1 at the transcriptional level in KB-TAX50 and KB-VIN10 cells Since a vast majority of patients enrolled in phase II clinical trials are usually at later cancer stages and possess multiple drug resistance our study may provide a novel YM155 combination alternative for clinical trials in the future
Date of Award2016 Aug 1
Original languageEnglish
SupervisorChun Hei Antonio Cheung (Supervisor)

Cite this