Hyperthermia and radiation reduce the toxic side-effects of bufadienolides for cancer therapy

Emam,Heba; Refaat,Alaa; Jawaid,Paras; Ur Rehman,Mati; Li,Peng; Zhao,Qing‑Li; Kondo,Takashi

doi:10.3892/ol.2017.6256

Hyperthermia and radiation reduce the toxic side-effects of bufadienolides for cancer therapy

Authors:
- Heba Emam
- Alaa Refaat
- Paras Jawaid
- Mati Ur Rehman
- Peng Li
- Qing‑Li Zhao
- Takashi Kondo
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Affiliations: Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930‑0194, Japan, Department of Cancer Cell Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930‑0194, Japan
Published online on: May 26, 2017 https://doi.org/10.3892/ol.2017.6256
Pages: 1035-1040

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Abstract

Bufadienolides are constituents of the traditional Chinese medicine Chan Su and are found in toad venom. Cardiovascular side‑effects are one of the limiting factors towards developing bufadienolides as chemotherapeutic agents. Thus, in the present study, low doses of bufalin and cinobufotalin, prominent members of the bufadienolides, were investigated for their cytotoxic activity in combination with hyperthermia (HT) or radiation (Rad) therapy. In addition, the underlying mechanism involved was investigated. A DNA fragmentation assay, viability assay and microscopic observation were primarily used to assess the effect of low doses of the two drugs in human lymphoma U937 cells. Furthermore, the effects of these drugs on the mitochondrial membrane potential (MMP) and apoptotic‑associated protein activation were investigated. HT/bufadienolide‑ and RT/bufadienolide‑treated samples significantly increased the DNA fragmentation percentile and decreased the MMP, as well as increasing the apoptotic features observed microscopically within a relatively short time (6 h) after treatment. The two combinations affected the expression of important apoptotic markers, including caspase‑3 and BH3 interacting domain death agonist. The findings of the current study confirm the additive effect of HT with this group of drugs, directing a novel therapeutic avenue for the clinical use of bufadienolides at lower doses with more restrained cardio toxic side‑effects.

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