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An In Vitro Model for Studying Cellular Transformation by Kaposi Sarcoma Herpesvirus
Published on: August 25, 2017
Efficient lytic induction of Kaposi's sarcoma-associated herpesvirus (KSHV) by the anthracyclines
Hyunju Kang1, Jaehyung Song2, Kwangman Choi3
1Targeted Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongwon, Chungbuk, Republic of Korea. College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
Abstract:
Lytic induction of latent Kaposi's sarcoma-associated herpesvirus (KSHV) has been considered as a therapeutic option for efficient treatment of several KSHV-associated malignancies. Here, we developed a robust high-throughput screening system that allows an easy and quantitative measurement of lytic induction of latent KSHV and discovered three anthracyclines as potent inducers from screen of FDA-approved drugs. Lytic induction of latent KSHV by three compounds was verified by the significant induction of lytic genes and subsequent production of infectious KSHV. Importantly, lytic induction by three compounds was much more efficient than that by sodium butyrate, a well-characterized inducer of KSHV lytic cycle. Mechanistically, the anthracyclines caused lytic induction of KSHV through apoptosis induced by their DNA intercalation rather than topoisomerase II inhibition. Consequently, our results clearly demonstrated a role of anthracyclines as effective lytic inducers of KSHV and also provided a molecular basis of their use for efficient treatment of diseases associated with KSHV infection.
Insights
Three FDA-approved anthracyclines were identified as potent inducers of Kaposi
Area of Science:
- Virology
- Oncology
- Drug Discovery
Background:
- Latent Kaposi's sarcoma-associated herpesvirus (KSHV) infection is linked to several malignancies.
- Lytic induction of KSHV is a potential therapeutic strategy for KSHV-associated diseases.
- Existing KSHV lytic induction methods require optimization for efficiency and scalability.
Purpose of the Study:
- To develop a high-throughput screening system for quantifying KSHV lytic induction.
- To identify FDA-approved drugs capable of inducing KSHV lytic replication.
- To elucidate the mechanism of KSHV lytic induction by identified compounds.
Main Methods:
- Development of a robust, quantitative high-throughput screening assay for KSHV lytic induction.
- Screening of FDA-approved drug libraries to identify novel KSHV inducers.
- Verification of lytic gene induction and infectious KSHV production.
- Mechanistic studies involving apoptosis and DNA intercalation assays.
Main Results:
- Three anthracycline compounds were identified as potent inducers of KSHV lytic replication.
- Lytic induction by these anthracyclines significantly exceeded that of sodium butyrate.
- Anthracyclines induced KSHV lytic replication via apoptosis mediated by DNA intercalation.
- Infectious KSHV production was confirmed following anthracycline treatment.
Conclusions:
- Anthracyclines are effective inducers of KSHV lytic replication.
- The identified compounds offer a promising therapeutic avenue for KSHV-associated diseases.
- Understanding the mechanism provides a basis for targeted KSHV therapies.
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