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Fibrates protect against vascular endothelial dysfunction induced by paclitaxel and carboplatin chemotherapy for cancer patients: a pilot study

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Abstract

Background

Although we previously demonstrated that paclitaxel and carboplatin chemotherapy (TCchem) is associated with vascular toxicities, the underlying mechanisms remain unclear. Cisplatin is known to inhibit PPARα following microvascular damage to the kidneys. The primary aim of this study was to evaluate whether TCchem induces vascular endothelial dysfunction via systemic PPARα deficiency. In addition, human umbilical vein endothelial cells (HUVECs) were used to elucidate the mechanisms responsible for TCchem-induced vascular toxicities.

Methods

This study enrolled 45 gynecological cancer patients with normal lipid profiles who underwent surgical treatment followed by TCchem. The elevated triglyceride (TG) group included patients (n = 19) who exhibited hypertriglyceridemia during TCchem, and the stable TG group (n = 15) included patients with a normal TG level. Eleven patients exhibiting hypertriglyceridemia during TCchem were administered bezafibrate (fibrate group). Endothelial dysfunction was evaluated based on flow-mediated dilation (FMD) values and serum pentraxin-3 levels measured before TCchem and immediately after the final TCchem. HUVECs were used to elucidate the biological mechanisms underlying the endothelial dysfunction induced by TCchem.

Results

The administration of TCchem induced hypertriglyceridemia in 66 percent of the participants, and bezafibrate reduced the serum TG levels. Meanwhile, the decrease in flow-mediated dilatation (%FMD) induced by TCchem improved following treatment with bezafibrate. The serum pentraxin-3 level increased rapidly after TCchem and decreased following bezafibrate treatment. An in vitro examination demonstrated TCchem attenuated nitric oxide production and PPARα activity in HUVECs, which was partially improved by treatment with bezafibrate.

Conclusion

Bezafibrate prevents endothelial dysfunction induced by TCchem via TG-dependent and TG-independent mechanisms.

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Abbreviations

PtChem:

Platinum-based chemotherapy

TG:

Triglycerides

TCchem:

Paclitaxel and carboplatin combination chemotherapy

FMD:

Flow-mediated dilation

PPARα:

Peroxisome proliferator-activated receptor-α

OC:

Ovarian cancer

EC:

Endometrial cancer

CVD:

Cardiovascular disease

LDL:

Low-density lipoprotein

HDL:

High-density lipoprotein

hsCRP:

High-sensitivity C-reactive protein

CDDP:

Cisplatin

CBDCA:

Carboplatin

PTX:

Paclitaxel

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Acknowledgments

We are grateful to Junko Hayashi, Akiko Hashimoto, and Kumiko Satoh for secretarial assistance. This study was supported by JSPS KAKENHI Grant Number 24592535.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka, 569-8686, Japan

    Ayako Watanabe, Akiko Tanabe, Risa Maruoka, Kiyoko Nakamura, Koji Hatta, Yoshihiro J. Ono, Yoshito Terai & Masahide Ohmichi

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  1. Ayako Watanabe
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  2. Akiko Tanabe
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  3. Risa Maruoka
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Correspondence to Akiko Tanabe.

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Watanabe, A., Tanabe, A., Maruoka, R. et al. Fibrates protect against vascular endothelial dysfunction induced by paclitaxel and carboplatin chemotherapy for cancer patients: a pilot study. Int J Clin Oncol 20, 829–838 (2015). https://doi.org/10.1007/s10147-014-0779-y

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  • DOI: https://doi.org/10.1007/s10147-014-0779-y

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