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Drug Discovery Using Evolutionary Similarities in Chemical Binding to Inhibit Patient-Derived Hepatocellular Carcinoma

Authors
 Jin Hong Lim  ;  Keunwan Park  ;  Kyung Hwa Choi  ;  Chan Wung Kim  ;  Jae Ha Lee  ;  Raymond Weicker  ;  Cheol-Ho Pan  ;  Seok-Mo Kim  ;  Ki Cheong Park 
Citation
 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol.23(14) : 7971, 2022-07 
Journal Title
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN
 1661-6596 
Issue Date
2022-07
MeSH
Calcium / metabolism ; Carcinoma, Hepatocellular* / drug therapy ; Carcinoma, Hepatocellular* / genetics ; Carcinoma, Hepatocellular* / metabolism ; Drug Discovery ; Endoplasmic Reticulum / metabolism ; Humans ; Liver Neoplasms* / drug therapy ; Liver Neoplasms* / genetics ; Liver Neoplasms* / metabolism ; Sarcoplasmic Reticulum / metabolism ; Sarcoplasmic Reticulum Calcium-Transporting ATPases / genetics ; Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism ; Thapsigargin / pharmacology
Keywords
cancer stem cells ; candidate 19 ; candidate 23 ; endoplasmic reticulum stress ; patient-derived anti-cancer drug-resistant hepatocellular carcinoma ; sarcoplasmic/endoplasmic reticulum calcium ATPase ; thapsigargin
Abstract
Drug resistance causes therapeutic failure in refractory cancer. Cancer drug resistance stems from various factors, such as patient heterogeneity and genetic alterations in somatic cancer cells, including those from identical tissues. Generally, resistance is intrinsic for cancers; however, cancer resistance becomes common owing to an increased drug treatment. Unfortunately, overcoming this issue is not yet possible. The present study aimed to evaluate a clinical approach using candidate compounds 19 and 23, which are sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) inhibitors, discovered using the evolutionary chemical binding similarity method. mRNA sequencing indicated SERCA as the dominant marker of patient-derived anti-cancer drug-resistant hepatocellular carcinoma (HCC), but not of patient-derived anti-cancer drug-sensitive HCC. Candidate compounds 19 and 23 led to significant tumor shrinkage in a tumor xenograft model of anti-cancer drug-resistant patient-derived HCC cells. Our results might be clinically significant for the development of novel combinatorial strategies that selectively and efficiently target highly malignant cells such as drug-resistant and cancer stem-like cells.
Files in This Item:
T202204422.pdf Download
DOI
10.3390/ijms23147971
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Seok Mo(김석모) ORCID logo https://orcid.org/0000-0001-8070-0573
Park, Ki Cheong(박기청) ORCID logo https://orcid.org/0000-0002-3435-3985
Lim, Jin Hong(임진홍)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/191676
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