Abstract
Hepatocellular carcinoma (HCC) is a significant health problem worldwide with poor prognosis. Drug repositioning represents a profitable strategy to accelerate drug discovery in the treatment of HCC. In this study, we developed a new approach for predicting therapeutic drugs for HCC based on tissue-specific pathways and identified three newly predicted drugs that are likely to be therapeutic drugs for the treatment of HCC. We validated these predicted drugs by analyzing their overlapping drug indications reported in PubMed literature. By using the cancer cell line data in the database, we constructed a Connectivity Map (CMap) profile similarity analysis and KEGG enrichment analysis on their related genes. By experimental validation, we found securinine and ajmaline significantly inhibited cell viability of HCC cells and induced apoptosis. Among them, securinine has lower toxicity to normal liver cell line, which is worthy of further research. Our results suggested that the proposed approach was effective and accurate for discovering novel therapeutic options for HCC. This method also could be used to indicate unmarked drug-disease associations in the Comparative Toxicogenomics Database. Meanwhile, our method could also be applied to predict the potential drugs for other types of tumors by changing the database.
Highlights
Hepatocellular carcinoma (HCC), called malignant hepatoma, is a major health problem and one of the leading causes of death worldwide, with an annual number of cases exceeding 841,000 [1]
Selecting therapeutic drugs that can be used for cancer treatment from existing drugs is a way to quickly obtain effective drugs, whereas the safety, dose and marginal effects of these drugs have been verified, and their clinical application will be faster than that of novel drug discovery
There have been a large number of successful cases of drug repositioning in the past few years
Summary
Hepatocellular carcinoma (HCC), called malignant hepatoma, is a major health problem and one of the leading causes of death worldwide, with an annual number of cases exceeding 841,000 [1]. HCC mostly affects patients with liver cirrhosis, which is the most common reason for the death of these patients. A few safe and effective therapeutic options are available to HCC patients, and the current drug discovery process is both costly and time inefficient [2]. It can take up to 15 years [3,4] and $ 2.8 billion to bring a single drug to the market [4]. In response to this slow process, drug repositioning has been used as a profitable and successful strategy for drug discovery and development. Well-known examples include minoxidil (originally designed for hypertension used to treat hair loss) [6], sildenafil (originally designed for pulmonary hypertension used to treat erectile dysfunction) [7], amphotericin B (originally designed for serious systemic fungal infections used to treat acute promyelocytic leukemia) [8], and atorvastatin (originally designed for cardiovascular disease used to treat Alzheimer’s disease) [9]
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