Inhibition of Intracellular ROS Accumulation by Formononetin Attenuates Cisplatin-Mediated Apoptosis in LLC-PK1 Cells.

Haesol Lee,Dahae Lee,Ji Song,You-Kyoung Choi,Ki Kang

doi:10.3390/ijms19030813

Abstract

Cisplatin is a well-known anticancer drug frequently used for treating solid tumors, including ovarian, testicular, bladder, and cervical tumors. However, usage of cisplatin has been limited because of its adverse effects, particularly nephrotoxicity. Therefore, the present study sought to investigate the protective effect of formononetin against cisplatin-induced cytotoxicity in LLC-PK1 pig kidney epithelial cells as well as the anticancer effect of cisplatin in three different human cervical cancer cell lines, including HeLa, SiHa, and CaSKi cells. We first demonstrated that formononetin strongly prevented cisplatin-induced LLC-PK1 cell death. Although formononetin had no anticancer effect, it did not interrupt the anticancer effect of cisplatin in human cervical carcinoma cell lines. Furthermore, the treatment with formononetin reduced reactive oxygen species (ROS) accumulation and chromatin condensation. The percentage of Annexin V-positive cells also increased following cisplatin treatment. Finally, formononetin-inhibited c-Jun N-terminal kinase (JNK) phosphorylation, cleavage of caspase-8 and caspase-3, and the ratio of Bax to Bcl-2 increased with cisplatin. Taken together, these findings suggest that formononetin may be a possible option to prevent nephrotoxicity induced by cisplatin during treatment for cervical cancer.

Highlights

Cisplatin is the most effective chemotherapeutic agent for various solid cancers, including testicular cancer, ovarian cancer, lung cancer, prostate cancer, breast cancer, and head and neck cancer [1,2,3]
Consistent with previous reports, our results showed that NAC prevented the decrease in exposed to cisplatin along with 10 μM and 25 μM formononetin for 24 h and stained with 2′,7′dichlorofluorescin diacetate (H2DCFDA), a membrane-permeable indicator for Reactive Oxygen Speiceses (ROS)
Dulbecco’s modified Eagle medium (DMEM) and RPMI1640 medium were purchased from Cellgro (Manassas, VA, USA)

Summary

Introduction

Cisplatin is the most effective chemotherapeutic agent for various solid cancers, including testicular cancer, ovarian cancer, lung cancer, prostate cancer, breast cancer, and head and neck cancer [1,2,3]. Cisplatin has strong anticancer effects, its usage has been limited as a result of its severe side effects. Nephrotoxicity is a major adverse effect of cisplatin treatment for cancers [4]. Cisplatin mainly induces epithelial cell damage in the kidney [5]. Cisplatin-mediated nephropathy is associated with various risk factors, including dosage and frequency of cisplatin administration. Cisplatin may contribute to the reduction of glomerular filtration rate and plasma magnesium concentration [6,7]

Methods

Discussion

Conclusion