Abstract
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.
Highlights
The standard treatment for advanced breast cancer includes doxorubicin (DOX), administered either as monotherapy or in combination with other cytotoxic or targeted drugs [1]
We investigated the effects of the combination of renieramycin M (RM) and DOX in estrogen receptor positive (ER+) MCF-7, an in model for the most common type of breastpurified cancer and determined Renieramycin is vitro a KCN-stabilized tetrahydroisoquinoline from the blue sponge the drugsp
We investigated the effects of the combination of RM and DOX in estrogen receptor positive (ER+ ) MCF-7, an in vitro model for the most common type of breast cancer and determined the drug ratio and regimen that will yield a synergistic effect
Summary
The standard treatment for advanced breast cancer includes doxorubicin (DOX), administered either as monotherapy or in combination with other cytotoxic or targeted drugs [1]. The generation of drug-resistant tumors after continued therapy is still inevitable, and this eventually narrows down. Mar. Drugs 2019, 17, 536; doi:10.3390/md17090536 www.mdpi.com/journal/marinedrugs drug for advanced soft tissue sarcoma and recurrent platinum-sensitive ovarian cancer. The renieramycins and ecteinascidins are the two major categories of the 1,2,3,4-tetrahydroisoquinoline alkaloids that have an anticancer effect. This warrants further investigation on the potential clinical utility of RM. A transcriptional structure–activity relationship (SAR) study and molecular network profiling revealed that RM and the ecteinascidin class of compounds induce apoptosis via a common
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