title: 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 CCl₄-induced disturbed intracellular GSH/GSSG balance. Shogaol and 4'-methoxygingerol showed considerable cytotoxic effects against HCT116, HeLa, HepG2 and MCF7 cells, with IC50 values ranging from 3.1 to 19.4 µM. Gingerol significantly enhanced the cytotoxic profile of doxorubicin against HepG₂ and Huh7, cells decreasing its IC50s by 10- and 4-fold, respectively. Cell cycle distribution was studied using DNA cytometry. Doxorubicin alone induced cell accumulation at S-phase and G₂/M-phase, while in combination with gingerol it significantly induced cell cycle arrest at the G₂/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.
authors.affiliation: Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21523, Saudi Arabia. alabassif@hotmail.com.
authors.forename: Fahad A
authors.initials: FA
authors.lastname: Al-Abbasi
authors.affiliation: Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21523, Saudi Arabia. mo0on_mo0ony@yahoo.com.
authors.forename: Eman A
authors.initials: EA
authors.lastname: Alghamdi
authors.affiliation: Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21523, Saudi Arabia. m-baghdadi@hotmail.com.|Research Centre, King Faisal Specialist Hospital and Research Centre, Jeddah 21499, Saudi Arabia. m-baghdadi@hotmail.com.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Baghdadi
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia. abdulmohsin@outlook.com.
authors.forename: Abdulmohsin J
authors.initials: AJ
authors.lastname: Alamoudi
authors.affiliation: Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia. ahalawany2003@yahoo.com.|Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt. ahalawany2003@yahoo.com.
authors.forename: Ali M
authors.initials: AM
authors.lastname: El-Halawany
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia. helbassossy@kau.edu.sa.|Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt. helbassossy@kau.edu.sa.
authors.forename: Hany M
authors.initials: HM
authors.lastname: El-Bassossy
authors.affiliation: Ministry of Health, Jeddah 21484, Saudi Arabia. alhaseeri@moh.gov.sa.
authors.forename: Ali H
authors.initials: AH
authors.lastname: Aseeri
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia. ahmedmalabd@pharma.asu.edu.eg.|Department of Pharmacology, Medical Division, National Research Centre, Giza 12622, Egypt. ahmedmalabd@pharma.asu.edu.eg.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Al-Abd
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology*; D000975:Antioxidants / Q000302:isolation & purification / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D002396:Catechols / Q000302:isolation & purification / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D004338:Drug Combinations; D004357:Drug Synergism; D005233:Fatty Alcohols / Q000302:isolation & purification / Q000494:pharmacology*; D045325:HCT116 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D046509:Tissue Culture Techniques; D014661:Vasoconstriction / Q000187:drug effects; D030521:Zingiberaceae / Q000737:chemistry*
chemical_list: D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D002396:Catechols; D004338:Drug Combinations; D005233:Fatty Alcohols; D004317:Doxorubicin; C007845:gingerol
keywords: diarylheptanoids; doxorubicin; gingerol; hydroxyphenylalkanes; liver cancer; vascular protection