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| Status |
Public on Jan 04, 2019 |
| Title |
Synergistic cytotoxicity of renieramycin M and doxorubicin in MCF-7 breast cancer cells |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
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 of RM and DOX after combination were reduced by up to 4-fold and 8-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 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 commonly downregulated 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 basis for in vivo studies and provides a rationale for using RM in combination with other anticancer drugs.
We used microarray-based transcriptome profiling to gain insights to the mechanism of action of the individual drugs and the synergistic drug combination
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| Overall design |
MCF-7 cells were treated with near IC50 concentrations of RM (6.25 nM), DOX (313 nM) and its combination (RM+DOX) for 60 h. Individual drug treatments and vehicle control were prepared in duplicates, while the combination treatment was prepared in triplicates.
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| Contributor(s) |
Tun JO, Salvador-Reyes LA, Velarde MC, Saito N, Suwanborirux K, Concepcion GP |
| Citation missing |
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| Submission date |
Jan 03, 2019 |
| Last update date |
Jan 05, 2019 |
| Contact name |
Jortan Oste Tun |
| E-mail(s) |
tunjortan@gmail.com
|
| Phone |
09178636600
|
| Organization name |
University of the Philippines
|
| Department |
Marine Science Institute
|
| Lab |
Concepcion
|
| Street address |
Velasquez Street
|
| City |
Quezon City |
| State/province |
National Capital Region |
| ZIP/Postal code |
1101 |
| Country |
Philippines |
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| Platforms (1) |
| GPL15207 |
[PrimeView] Affymetrix Human Gene Expression Array |
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| Samples (9)
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| Relations |
| BioProject |
PRJNA512621 |
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