Spatial Lipidomics Reveals Anticancer Mechanisms of Bufalin in Combination with Cinobufagin in Tumor-Bearing Mice.

Jinghui Zhang,Yong Chen,Yongjiang Wu,Zongwei Cai,Lilong Jiang,Guodong Cao,Yang Chen,Xuesong Liu,Zhiyi Yang,Zhongjian Chen,Peisi Xie,Yanjun Hong

doi:10.3389/fphar.2020.593815

Jinghui Zhang, Yong Chen + Show 10 more

Open Access

https://doi.org/10.3389/fphar.2020.593815

Copy DOI

Abstract

Bufalin (BFL) and cinobufagin (CBF) are the principal bioactive constituents of Chansu, a widely used traditional Chinese medicine (TCM). The synergistic effects of potential active components are responsible for the bioactivities of TCM. Our results showed that the cotreatment with BFL and CBF confers superior anticancer efficacy compared to monotreatment. To reveal the underlying mechanisms of their cotreatment, an integrated method composed of mass spectrometry-based lipidomics and matrix-assisted laser desorption/ionization mass spectrometry imaging was used to delineate the responses of tumor-bearing mice treated with BFL and CBF individually or in combination. The cotreatment with BFL and CBF modulated the sphingolipid metabolism and glycerophospholipid metabolism, and subsequently led to mitochondria-driven apoptosis and systemic disruption of biomembranes in tumor cells. Furthermore, we found that the disturbed lipid markers were mainly located in the non-necrotic tumor areas, the essential parts for the formation of solid tumor framework. Together, our findings revealed what occurred in tumor in response to the treatment of BFL and CBF, from lipids to enzymes, and thus provide insights into the critical role of lipid reprogramming in the satisfactory anticancer effect of BFL in combination with CBF.

Highlights

Hepatoma is a severe malignancy usually with poor prognosis (Thomas and Zhu, 2005)
The cotreatment with BFL and CBF led to stronger inhibition of tumor growth, which is similar to the therapeutic efficacy of cisplatin
We observed the loss of body weight in the cisplatin treated group, which is consistent with previous reports (Garcia et al, 2013; Su et al, 2014). α-fetoprotein (AFP) was one of the most important indicators for hepatoma (Woodfield et al, 2017)

Summary

Introduction

Hepatoma is a severe malignancy usually with poor prognosis (Thomas and Zhu, 2005). hepatoma can be surgically resected, chemotherapy has an irreplaceable status and function for patients in advanced stages (El-Serag et al, 2008). A sterilized extract of Chansu, has been marketed and used in clinical They have been widely used for the treatment of Bufalin and Cinobufagin Anticancer Mechanisms patients with various types of cancer, especially in liver cancer (Huang et al, 2020). We detected BFL and CBF in Huachansu capsules by ultra high performance liquid chromatography (Supplementary Figure S2). Their individual anticancer effects were associated with a downregulation of the prosurvival proteins Bcl-2, and an upregulation of the proapoptotic protein Fas and Bax (Qi et al, 2011; Shen et al, 2014). More emphasis should be put on the mechanisms of the combination of BFL and CBF

Methods

Results

Discussion

Conclusion