A novel radiolytic rotenone derivative, rotenoisin A, displays potent anticarcinogenic activity in breast cancer cells

Abstract

Chemotherapy for cancer treatment has therapeutic limitations, such as drug resistance, excessive toxic effects and undesirable adverse effects. Therefore, efforts to improve the safety and efficacy of chemotherapeutic agents are essential. Ionizing radiation can improve physiological and pharmacological properties by transforming structural modifications of the drug. In this study, in order to reduce the adverse effects of rotenone and increase anticancer activity, a new radiolytic rotenone derivative called rotenoisin A was generated through radiolytic transformation. Our findings showed that rotenoisin A inhibited the proliferation of breast cancer cells and increased the rate of apoptosis, whereas it had no inhibitory effect on primary epidermal keratinocytes compared with rotenone. Moreover, rotenoisin A-induced DNA damage by increasing reactive oxygen species (ROS) accumulation. It was also confirmed not only to alter the composition ratio of mitochondrial proteins, but also to result in structural and functional changes. The anticancer effect and molecular signalling mechanisms of rotenoisin A were consistent with those of rotenone, as previously reported. Our study suggests that radiolytic transformation of highly toxic compounds may be an alternative strategy for maintaining anticancer effects and reducing the toxicity of the parent compound.

Novel aminopyridazine derivative of minaprine modified by radiolysis presents potent anti-inflammatory effects in LPS-stimulated RAW 264.7 and DH82 macrophage cells

“…In a recent study, chrysin and luteolin showed improved anti-in ammatory activities in vitro and in vivo induced by γ-irradiation, and the chemical structure of hydroxyalkyl-substituted compounds was identi ed 12,21 . In addition, radiolytic transformation of alkaloids and steroids showed potent enhanced anti-cancer effects in melanoma, breast, liver, and lung cancer 11,[22][23][24][25] .…”

Inhibitory Effects of Thermolysis Transformation Products of Rotenone on Nitric Oxide Production

“…During the last decade, the structural transformation of rotenone to improve its biological capacity has been achieved using microbial and gamma irradiation [ 9 , 13 ]. Previous studies have revealed that rotenone derivatives induced by hydroxylation and oxidation reactions have potent anti-adipogenic and anti-cancer effects [ 10 , 11 , 12 ]. In this study, the structural modification of rotenone using thermolysis showed potentially enhanced anti-inflammatory effects against nitric oxide production, indicating that degradation and hydroxylation at the C-12 of rotenone are correlated with an increase in biological capacities.…”

“…Several isoflavone derivatives recently derived from rotenone were found to exhibit a range of biological activities, including anti-fungal, anti-bacterial, anti-malarial, and anti-cancer properties [ 7 , 8 ]. Park et al (2012) used the gamma-irradiation technique to induce molecular modification of rotenone, to structurally determined novel rotenoisins A and B [ 9 ] and reported potent anti-adipogenic and anti-cancer capacities [ 10 , 11 , 12 ]. In addition, hydrated rotenone derivatives induced by microbial transformation have been reported to exhibit potent anti-tumor efficacy [ 13 ].…”

Transformation of nomifensine using ionizing radiation and exploration of its anticancer effects in MCF‑7 cells

“…Several pieces of research have been conducted for increasing the efficacy of biomaterials using radiation transformation technology (11,12). In a previous study, the authors irradiated rotenone with gamma rays and confirmed that its by-product, rotenoisin B, a radiolytic derivative, was produced, which inhibited proliferation in hepatocarcinoma (13). In addition, it was confirmed that radiation-irradiated Kenalog ® also increased the apoptotic effect of melanoma compared with Kanalog ® , the original material (14).…”