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

Overview

Journal Mar Drugs

Publisher MDPI

Specialties Biology
Pharmacology

Date 2019 Sep 19

PMID 31527453

Citations 12

Authors

Jortan O Tun

Lilibeth A Salvador-Reyes

Michael C Velarde

Naoki Saito

Khanit Suwanborirux

Gisela P Concepcion

Affiliations

Soon will be listed here.

Abstract

Renieramycin M (RM) is a KCN-stabilized tetrahydroisoquinoline purified from the blue sponge sp., with nanomolar ICs 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 IC 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.

Citing Articles

Mechanistic Approach into 1,2,3-triazoles-based IIIM(S)-RS98 Mediated Apoptosis in Lung Cancer Cells.

Dolkar R, Paudwal G, Singh D, Behera C, Malik S, Ali S AAPS J. 2025; 27(1):35.

PMID: 39900819 DOI: 10.1208/s12248-025-01018-9.

Deep-Sea Sponges and Corals off the Western Coast of Florida-Intracellular Mechanisms of Action of Bioactive Compounds and Technological Advances Supporting the Drug Discovery Pipeline.

Iskandar M, Ruiz-Houston K, Bracco S, Sharkasi S, Calabi Villarroel C, Desai M Mar Drugs. 2023; 21(12).

PMID: 38132936 PMC: 10744787. DOI: 10.3390/md21120615.

MiR-145 inhibits cell migration and increases paclitaxel chemosensitivity in prostate cancer cells.

Tohidast M, Memari N, Amini M, Hosseini S, Jebelli A, Doustvandi M Iran J Basic Med Sci. 2023; 26(11):1350-1359.

PMID: 37886001 PMC: 10598815. DOI: 10.22038/IJBMS.2023.70878.15397.

Synergistic combination of doxorubicin with hydralazine, and disulfiram against MCF-7 breast cancer cell line.

Lafi Z, Alshaer W, Gharaibeh L, Alqudah D, AlQuaissi B, Bashaireh B PLoS One. 2023; 18(9):e0291981.

PMID: 37768997 PMC: 10538757. DOI: 10.1371/journal.pone.0291981.

Co-delivery of doxorubicin and hydroxychloroquine via chitosan/alginate nanoparticles for blocking autophagy and enhancing chemotherapy in breast cancer therapy.

Zhang H, Xue Q, Zhou Z, He N, Li S, Zhao C Front Pharmacol. 2023; 14:1176232.

PMID: 37229260 PMC: 10203398. DOI: 10.3389/fphar.2023.1176232.

References

Pommier Y, Leo E, Zhang H, Marchand C . DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem Biol. 2010; 17(5):421-33. PMC: 7316379. DOI: 10.1016/j.chembiol.2010.04.012. View

Pritchard J, Bruno P, Gilbert L, Capron K, Lauffenburger D, Hemann M . Defining principles of combination drug mechanisms of action. Proc Natl Acad Sci U S A. 2012; 110(2):E170-9. PMC: 3545813. DOI: 10.1073/pnas.1210419110. View

Tabunoki H, Saito N, Suwanborirux K, Charupant K, Satoh J . Molecular network profiling of U373MG human glioblastoma cells following induction of apoptosis by novel marine-derived anti-cancer 1,2,3,4-tetrahydroisoquinoline alkaloids. Cancer Cell Int. 2012; 12(1):14. PMC: 3441782. DOI: 10.1186/1475-2867-12-14. View

Focaccetti C, Bruno A, Magnani E, Bartolini D, Principi E, Dallaglio K . Effects of 5-fluorouracil on morphology, cell cycle, proliferation, apoptosis, autophagy and ROS production in endothelial cells and cardiomyocytes. PLoS One. 2015; 10(2):e0115686. PMC: 4324934. DOI: 10.1371/journal.pone.0115686. View

Mitra S, Hanson D, Schlaepfer D . Focal adhesion kinase: in command and control of cell motility. Nat Rev Mol Cell Biol. 2005; 6(1):56-68. DOI: 10.1038/nrm1549. View

David-Cordonnier M, Gajate C, Olmea O, Laine W, de la Iglesia-Vicente J, Perez C . DNA and non-DNA targets in the mechanism of action of the antitumor drug trabectedin. Chem Biol. 2005; 12(11):1201-10. DOI: 10.1016/j.chembiol.2005.08.009. View

Ivy S, de Bono J, Kohn E . The 'Pushmi-Pullyu' of DNA REPAIR: Clinical Synthetic Lethality. Trends Cancer. 2017; 2(11):646-656. PMC: 5527674. DOI: 10.1016/j.trecan.2016.10.014. View

Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A . ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics. 2009; 25(8):1091-3. PMC: 2666812. DOI: 10.1093/bioinformatics/btp101. View

Micallef L, Rodgers P . eulerAPE: drawing area-proportional 3-Venn diagrams using ellipses. PLoS One. 2014; 9(7):e101717. PMC: 4102485. DOI: 10.1371/journal.pone.0101717. View

10.

Symington L, Gautier J . Double-strand break end resection and repair pathway choice. Annu Rev Genet. 2011; 45:247-71. DOI: 10.1146/annurev-genet-110410-132435. View

11.

Halim H, Chunhacha P, Suwanborirux K, Chanvorachote P . Anticancer and antimetastatic activities of Renieramycin M, a marine tetrahydroisoquinoline alkaloid, in human non-small cell lung cancer cells. Anticancer Res. 2011; 31(1):193-201. View

12.

Takahashi N, Li W, Banerjee D, Scotto K, Bertino J . Sequence-dependent enhancement of cytotoxicity produced by ecteinascidin 743 (ET-743) with doxorubicin or paclitaxel in soft tissue sarcoma cells. Clin Cancer Res. 2001; 7(10):3251-7. View

13.

Xing C, LaPorte J, Barbay J, Myers A . Identification of GAPDH as a protein target of the saframycin antiproliferative agents. Proc Natl Acad Sci U S A. 2004; 101(16):5862-6. PMC: 395888. DOI: 10.1073/pnas.0307476101. View

14.

Takahashi N, Li W, Banerjee D, Guan Y, Brennan M, Chou T . Sequence-dependent synergistic cytotoxicity of ecteinascidin-743 and paclitaxel in human breast cancer cell lines in vitro and in vivo. Cancer Res. 2002; 62(23):6909-15. View

15.

Mayer L, Janoff A . Optimizing combination chemotherapy by controlling drug ratios. Mol Interv. 2007; 7(4):216-23. DOI: 10.1124/mi.7.4.8. View

16.

Mi H, Huang X, Muruganujan A, Tang H, Mills C, Kang D . PANTHER version 11: expanded annotation data from Gene Ontology and Reactome pathways, and data analysis tool enhancements. Nucleic Acids Res. 2016; 45(D1):D183-D189. PMC: 5210595. DOI: 10.1093/nar/gkw1138. View

17.

Knopfova L, Biglieri E, Volodko N, Masarik M, Hermanova M, Glaus Garzon J . Transcription factor c-Myb inhibits breast cancer lung metastasis by suppression of tumor cell seeding. Oncogene. 2017; 37(8):1020-1030. PMC: 6711763. DOI: 10.1038/onc.2017.392. View

18.

Sartori A, Lukas C, Coates J, Mistrik M, Fu S, Bartek J . Human CtIP promotes DNA end resection. Nature. 2007; 450(7169):509-14. PMC: 2409435. DOI: 10.1038/nature06337. View

19.

McDermott M, Chumanevich A, Lim C, Liang J, Chen M, Altilia S . Inhibition of CDK8 mediator kinase suppresses estrogen dependent transcription and the growth of estrogen receptor positive breast cancer. Oncotarget. 2017; 8(8):12558-12575. PMC: 5355036. DOI: 10.18632/oncotarget.14894. View

20.

Farmer H, McCabe N, Lord C, Tutt A, Johnson D, Richardson T . Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005; 434(7035):917-21. DOI: 10.1038/nature03445. View