title: Breast cancer drugs dampen vascular functions by interfering with nitric oxide signaling in endothelium.
abstract: Widely used chemotherapeutic breast cancer drugs such as Tamoxifen citrate (TC), Capecitabine (CP) and Epirubicin (EP) are known to cause various cardiovascular side-effects among long term cancer survivors. Vascular modulation warrants nitric oxide (NO) signal transduction, which targets the vascular endothelium. We hypothesize that TC, CP and EP interference with the nitric oxide downstream signaling specifically, could lead to cardiovascular dysfunctions. The results demonstrate that while all three drugs attenuate NO and cyclic guanosine mono-phosphate (cGMP) production in endothelial cells, they caused elevated levels of NO in the plasma and RBC. However, PBMC and platelets did not show any significant changes under treatment. This implies that the drug effects are specific to the endothelium. Altered eNOS and phosphorylated eNOS (Ser-1177) localization patterns in endothelial cells were observed following drug treatments. Similarly, the expression of phosphorylated eNOS (Ser-1177) protein was decreased under the treatment of drugs. Altered actin polymerization was also observed following drug treatment, while addition of SpNO and 8Br-cGMP reversed this effect. Incubation with the drugs decreased endothelial cell migration whereas addition of YC-1, SC and 8Br-cGMP recovered the effect. Additionally molecular docking studies showed that all three drugs exhibited a strong binding affinity with the catalytic domain of human sGC. In conclusion, results indicate that TC, CP and EP cause endothelial dysfunctions via the NO-sGC-cGMP pathway and these effects could be recovered using pharmaceutical agonists of NO signaling pathway. Further, the study proposes a combination therapy of chemotherapeutic drugs and cGMP analogs, which would confer protection against chemotherapy mediated vascular dysfunctions in cancer patients.
authors.affiliation: Vascular Biology Lab, AU-KBC Research Centre, Anna University, Chennai, India.
authors.forename: Palanivel
authors.initials: P
authors.lastname: Gajalakshmi
authors.forename: Mani Krishna
authors.initials: MK
authors.lastname: Priya
authors.forename: Thangaraj
authors.initials: T
authors.lastname: Pradeep
authors.forename: Jyotirmaya
authors.initials: J
authors.lastname: Behera
authors.forename: Kandasamy
authors.initials: K
authors.lastname: Muthumani
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Madhuwanti
authors.forename: Uttara
authors.initials: U
authors.lastname: Saran
authors.forename: Suvro
authors.initials: S
authors.lastname: Chatterjee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D000069287:Capecitabine; D002417:Cattle; D002478:Cells, Cultured; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects*; D015251:Epirubicin / Q000633:toxicity*; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000633:toxicity; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013629:Tamoxifen / Q000633:toxicity*
chemical_list: D000970:Antineoplastic Agents; D013629:Tamoxifen; D003841:Deoxycytidine; D009569:Nitric Oxide; D015251:Epirubicin; D000069287:Capecitabine; D052250:Nitric Oxide Synthase Type III; D005472:Fluorouracil