TY - JOUR
T1 - Mechanistic basis of a combination d-penicillamine and platinum drugs synergistically inhibits tumor growth in oxaliplatin-resistant human cervical cancer cells in vitro and in vivo
AU - Chen, Szu Jung
AU - Kuo, Ching Chuan
AU - Pan, Hsin Yi
AU - Tsou, Tsui Chun
AU - Yeh, Szu Ching
AU - Chang, Jang Yang
N1 - Funding Information:
This study was supported by the following grants: the Ministry of Health and Welfare, Taiwan ( CA103-SP-01 ), the National Health Research Institutes ( CA-103-PP-22 ), the National Research Program for Biopharmaceuticals ( MOST 103-2325-B-400-012 ), and the Ministry of Education, Taiwan, R.O.C. (Aim for the Top University Project at National Cheng Kung University) ( D103-35A09 ).
Publisher Copyright:
© 2015 Elsevier Inc. All rights reserved.
PY - 2015/5
Y1 - 2015/5
N2 - The platinum-based regimen is the front-line treatment of chemotherapy. However, development of platinum resistance often causes therapeutic failure in this disease. We previously have generated an oxaliplatin-resistant subline, named S3, from human cervical carcinoma SiHa cells, and its resistant phenotype was well-characterized. In the present study, we aimed to identify the novel therapeutic strategy by combining copper chelator d-penicillamine with oxaliplatin, and to elucidate the underlying mechanisms for overcoming oxaliplatin resistance. As the result, d-penicillamine exerted synergistic killing effects only in S3 cells when combined with oxaliplatin and cisplatin by using Chou-Talalay method. Further study showed that the amounts of platinum DNA adduct formed were positively correlated to the percentage of cell death in S3 cells when co-treated d-penicillamine with oxaliplatin and cisplatin. d-penicillamine promoted copper influx transporter hCtr1 expression through upregulation of Sp1. Sp1 overexpression induced p53 translocation from nucleus to cytosol and caused p53 degradation through ubiquitination, which subsequently suppressed the expression of the copper efflux transporter ATP7A. Importantly, co-treatment of cisplatin with d-penicillamine enhanced oxaliplatin-elicited antitumor effect in the oxalipatin-resistant S3 xenograft tumors, but not found in SiHa xenograft model. Notably, Mice received d-penicillamine alone or in combination of d-penicillamine ad oxalipatin, increased hCtrl protein level in S3 xenograft tumor, however, the protein level of ATP7A was decreased. Taken together, this study provides insight into that the co-manipulation of hCtrl and ATP7A by d-penicillamine could increase the therapeutic efficacy of platinum drugs in oxaliplatin resistant tumors, especially in resistant phenotype with downexpression of hCtrl and overexpression of ATP7A.
AB - The platinum-based regimen is the front-line treatment of chemotherapy. However, development of platinum resistance often causes therapeutic failure in this disease. We previously have generated an oxaliplatin-resistant subline, named S3, from human cervical carcinoma SiHa cells, and its resistant phenotype was well-characterized. In the present study, we aimed to identify the novel therapeutic strategy by combining copper chelator d-penicillamine with oxaliplatin, and to elucidate the underlying mechanisms for overcoming oxaliplatin resistance. As the result, d-penicillamine exerted synergistic killing effects only in S3 cells when combined with oxaliplatin and cisplatin by using Chou-Talalay method. Further study showed that the amounts of platinum DNA adduct formed were positively correlated to the percentage of cell death in S3 cells when co-treated d-penicillamine with oxaliplatin and cisplatin. d-penicillamine promoted copper influx transporter hCtr1 expression through upregulation of Sp1. Sp1 overexpression induced p53 translocation from nucleus to cytosol and caused p53 degradation through ubiquitination, which subsequently suppressed the expression of the copper efflux transporter ATP7A. Importantly, co-treatment of cisplatin with d-penicillamine enhanced oxaliplatin-elicited antitumor effect in the oxalipatin-resistant S3 xenograft tumors, but not found in SiHa xenograft model. Notably, Mice received d-penicillamine alone or in combination of d-penicillamine ad oxalipatin, increased hCtrl protein level in S3 xenograft tumor, however, the protein level of ATP7A was decreased. Taken together, this study provides insight into that the co-manipulation of hCtrl and ATP7A by d-penicillamine could increase the therapeutic efficacy of platinum drugs in oxaliplatin resistant tumors, especially in resistant phenotype with downexpression of hCtrl and overexpression of ATP7A.
KW - ATP7A
KW - Copper transporter
KW - D-penicillamine
KW - Oxaliplatin resistance
KW - p53
KW - Specificity protein 1 Sp1
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U2 - 10.1016/j.bcp.2015.03.006
DO - 10.1016/j.bcp.2015.03.006
M3 - Article
C2 - 25801007
AN - SCOPUS:84930883628
SN - 0006-2952
VL - 95
SP - 28
EP - 37
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 1
ER -
