Gingerol Synergizes the Cytotoxic Effects of Doxorubicin against Liver Cancer Cells and Protects from Its Vascular Toxicity

Abstract

Hydroxyphenylalkanes and diarylheptanoids possess potential therapeutic value in different pathophysiological conditions, such as malignancy. In the current study, naturally isolated hydroxyphenylalkane and diarylheptanoid compounds were investigated for potential chemo-modulatory effects in addition to potential vascular protective roles with doxorubicin. Diarylheptanoids showed stronger antioxidant effects, in comparison to hydroxyphenylalkanes, as demonstrated by DPPH assay and amelioration of CCl 4 -induced disturbed intracellular GSH/GSSG balance. Shogaol and 4 1 -methoxygingerol showed considerable cytotoxic effects against HCT116, HeLa, HepG2 and MCF7 cells, with IC 50 values ranging from 3.1 to 19.4 µM. Gingerol significantly enhanced the cytotoxic profile of doxorubicin against HepG 2 and Huh7, cells decreasing its IC 50 s by 10-and 4-fold, respectively. Cell cycle distribution was studied using DNA cytometry. Doxorubicin alone induced cell accumulation at S-phase and G 2 /M-phase, while in combination with gingerol it significantly induced cell cycle arrest at the G 2 /M-phase. Additionally, the vascular protective effect of gingerol against doxorubicin (10 µM) was examined on isolated aortic rings. Co-incubation with 6-gingerol (30 µM) completely blocked the exaggerated vasoconstriction and impaired vascular relaxation induced by doxorubicin. In conclusion, despite its relatively weak antioxidant properties, gingerol protected from DOX-induced vascular damage, apparently not through a ROS scavenging mechanism. Besides, gingerol synergized the cytotoxic effects of DOX against liver cancer cells without influencing the cellular pharmacokinetics.

PG-Priming Enhances Doxorubicin Influx to Trigger Necrotic and Autophagic Cell Death in Oral Squamous Cell Carcinoma

“…Nitidine chloride, an alkaloid, synergized Dox cytotoxicity in breast cancer cell through PI3K/Akt signaling pathway [ 54 ]. Gingerol synergized Dox against liver cancer cells, leading to G2/M arrest [ 55 ]. Not only pure compounds; phenolic extract of flaxseed oil also promoted Dox efficacy against breast cancer cells [ 56 ].…”

MicroRNA‐mediated suppression of P‐glycoprotein by quantum dots in lung cancer cells

“…As a typical heavy metal ion, Cd 2+ are believed to enter cells via ion channels and bind non-specifically to sulfhydryl groups to dysregulate multiple cellular functions to ultimately produce cytotoxicity depending on the Cd concentration, duration of exposure, and cell type (Rani, Kumar, Lal, & Pant, 2014). Cytotoxicity of DOX, on the other hand, relies on topoisomerase inhibition, DNA intercalation, and ROS generation in cancer cells (Al-Abbasi et al, 2016;Swift et al, 2008). Nevertheless, both Cd 2+ and DOX have been found to induce the expression of P-gp in mammalian cells (Tian et al, 2017) and MDR cancer cells (Mariagrazia et al, 1996;Toffoli, Corona, Gigante, & Boiocchi, 1996), respectively.…”

Protective effects of olive in renal failure; a review on current knowledge

“…The antitumor effect of doxorubicin has been introduced for the selection of this compound in order to deal with a range of cancers, such as leukemia, lymphoma, and solid tumors in humans (3). However, the limiting factor in the use of doxorubicin in the treatment of cancer is its toxic effects on vital organs, such as the heart, kidneys, and liver (4,5). One of the main damaging mechanisms of this drug to various tissues including the heart, liver, and kidneys is related to the oxidative stress and reduction of antioxidants, and also increased oxidants in particular reactive oxygen species (6).…”