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Open AccessArticle

Synergistic Cytotoxicity of Renieramycin M and Doxorubicin in MCF-7 Breast Cancer Cells

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The Marine Science Institute, University of the Philippines Diliman, Quezon City 1101, Philippines
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Philippine Genome Center, University of the Philippines Diliman, Quezon City 1101, Philippines
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Institute of Biology, University of the Philippines Diliman, Quezon City 1101, Philippines
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Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University, Tokyo 204-8588, Japan
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Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Center for Bioactive Natural Products from Marine Organisms and Endophytic Fungi (BNPME), Chulalongkorn University, Pathumwan, Bangkok 10330, Thailand
*
Authors to whom correspondence should be addressed.
Mar. Drugs 2019, 17(9), 536; https://doi.org/10.3390/md17090536
Received: 23 July 2019 / Revised: 5 August 2019 / Accepted: 7 August 2019 / Published: 16 September 2019
Renieramycin M (RM) is a KCN-stabilized tetrahydroisoquinoline purified from the blue sponge Xestospongia sp., with nanomolar IC50s against several cancer cell lines. Our goal is to evaluate its combination effects with doxorubicin (DOX) in estrogen receptor positive MCF-7 breast cancer cells. MCF-7 cells were treated simultaneously or sequentially with various combination ratios of RM and DOX for 72 h. Cell viability was determined using the MTT assay. Synergism or antagonism was determined using curve-shift analysis, combination index method and isobologram analysis. Synergism was observed with pharmacologically achievable concentrations of DOX when administered simultaneously, but not sequentially. The IC95 values of RM and DOX after combination were reduced by up to four-fold and eight-fold, respectively. To gain insights on the mechanism of synergy, real-time profiling, cell cycle analysis, apoptosis assays, and transcriptome analysis were conducted. The combination treatment displayed a similar profile with DNA-damaging agents and induced a greater and faster cell killing. The combination treatment also showed an increase in apoptosis. DOX induced S and G2/M arrest while RM did not induce significant changes in the cell cycle. DNA replication and repair genes were downregulated commonly by RM and DOX. p53 signaling and cell cycle checkpoints were regulated by DOX while ErbB/PI3K-Akt, integrin and focal adhesion signaling were regulated by RM upon combination. Genes involved in cytochrome C release and interferon gamma signaling were regulated specifically in the combination treatment. This study serves as a basis for in vivo studies and provides a rationale for using RM in combination with other anticancer drugs. View Full-Text
Keywords: renieramycin M; doxorubicin; synergistic combination chemotherapy; real-time profiling; cell cycle; gene expression profiling; apoptosis; breast cancer; blue sponge; DNA damage response renieramycin M; doxorubicin; synergistic combination chemotherapy; real-time profiling; cell cycle; gene expression profiling; apoptosis; breast cancer; blue sponge; DNA damage response
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MDPI and ACS Style

Tun, J.O.; Salvador-Reyes, L.A.; Velarde, M.C.; Saito, N.; Suwanborirux, K.; Concepcion, G.P. Synergistic Cytotoxicity of Renieramycin M and Doxorubicin in MCF-7 Breast Cancer Cells. Mar. Drugs 2019, 17, 536.

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