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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 ofmore » 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. - Highlights: • 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.« less

Authors:
; ; ; ; ; ; ;
Publication Date:
OSTI Identifier:
22285303
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 269; Journal Issue: 2; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; ACTIN; CHEMOTHERAPY; DRUGS; ENDOTHELIUM; GUANOSINE; MAMMARY GLANDS; NEOPLASMS; NITRIC OXIDE; SIDE EFFECTS; SIGNALS; TAMOXIFEN; VASOCONSTRICTION

Citation Formats

Gajalakshmi, Palanivel, Priya, Mani Krishna, Pradeep, Thangaraj, Behera, Jyotirmaya, Muthumani, Kandasamy, Madhuwanti, Srinivasan, Saran, Uttara, and Chatterjee, Suvro. Breast cancer drugs dampen vascular functions by interfering with nitric oxide signaling in endothelium. United States: N. p., 2013. Web. doi:10.1016/J.TAAP.2013.03.011.
Gajalakshmi, Palanivel, Priya, Mani Krishna, Pradeep, Thangaraj, Behera, Jyotirmaya, Muthumani, Kandasamy, Madhuwanti, Srinivasan, Saran, Uttara, & Chatterjee, Suvro. Breast cancer drugs dampen vascular functions by interfering with nitric oxide signaling in endothelium. United States. https://doi.org/10.1016/J.TAAP.2013.03.011
Gajalakshmi, Palanivel, Priya, Mani Krishna, Pradeep, Thangaraj, Behera, Jyotirmaya, Muthumani, Kandasamy, Madhuwanti, Srinivasan, Saran, Uttara, and Chatterjee, Suvro. 2013. "Breast cancer drugs dampen vascular functions by interfering with nitric oxide signaling in endothelium". United States. https://doi.org/10.1016/J.TAAP.2013.03.011.
@article{osti_22285303,
title = {Breast cancer drugs dampen vascular functions by interfering with nitric oxide signaling in endothelium},
author = {Gajalakshmi, Palanivel and Priya, Mani Krishna and Pradeep, Thangaraj and Behera, Jyotirmaya and Muthumani, Kandasamy and Madhuwanti, Srinivasan and Saran, Uttara and Chatterjee, Suvro},
abstractNote = {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. - Highlights: • 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.},
doi = {10.1016/J.TAAP.2013.03.011},
url = {https://www.osti.gov/biblio/22285303}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 2,
volume = 269,
place = {United States},
year = {Sat Jun 01 00:00:00 EDT 2013},
month = {Sat Jun 01 00:00:00 EDT 2013}
}