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- Title
Drug Discovery Using Evolutionary Similarities in Chemical Binding to Inhibit Patient-Derived Hepatocellular Carcinoma.
- Authors
Lim, Jin Hong; Park, Keunwan; Choi, Kyung Hwa; Kim, Chan Wung; Lee, Jae Ha; Weicker, Raymond; Pan, Cheol-Ho; Kim, Seok-Mo; Park, Ki Cheong
- 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.
- Subjects
HEPATOCELLULAR carcinoma; DRUG discovery; SOMATIC cells; CANCER cells; ENDOPLASMIC reticulum; DRUG resistance in cancer cells
- Publication
International Journal of Molecular Sciences, 2022, Vol 23, Issue 14, p7971
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms23147971