Breast cancer drugs dampen vascular functions by interfering with nitric oxide signaling in endothelium

• Published in: Toxicology and applied pharmacology 2013-06, Vol.269 (2), p.121-131
• Main Authors: Gajalakshmi, Palanivel, Priya, Mani Krishna, Pradeep, Thangaraj, Behera, Jyotirmaya, Muthumani, Kandasamy, Madhuwanti, Srinivasan, Saran, Uttara, Chatterjee, Suvro
• Format: Article
• Language: English
• Subjects: ACTIN; Animals; Antineoplastic Agents - toxicity; Biological and medical sciences; Capecitabine; Cattle; Cells, Cultured; cGMP; CHEMOTHERAPY; Deoxycytidine - analogs & derivatives; Deoxycytidine - toxicity; Dose-Response Relationship, Drug; DRUGS; Endothelial Cells - drug effects; ENDOTHELIUM; Epirubicin; Epirubicin - toxicity; Fluorouracil - analogs & derivatives; Fluorouracil - toxicity; Gene Expression Regulation, Enzymologic; GUANOSINE; Gynecology. Andrology. Obstetrics; Humans; Mammary gland diseases; MAMMARY GLANDS; Medical sciences; Models, Molecular; Molecular Structure; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); NEOPLASMS; NITRIC OXIDE; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - genetics; Nitric Oxide Synthase Type III - metabolism; Protein Conformation; Protein Structure, Tertiary; RADIOLOGY AND NUCLEAR MEDICINE; SIDE EFFECTS; Signal Transduction - drug effects; Signal Transduction - physiology; SIGNALS; TAMOXIFEN; Tamoxifen - toxicity; Tamoxifen citrate; Toxicology; Tumors; VASOCONSTRICTION
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2013.03.011

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. •NO production is reduced in endothelial cells under breast cancer drug treatment.•Cellular cGMP level is decreased under the treatments of breast cancer drugs.•Breast cancer drugs induce vasoconstriction by interfering with NO pathway.•NO donors, cGMP analogs rescue breast cancer drug induced endothelial dysfunctions.