Synergistic Growth Inhibitory Effect of Flavonol–kaempferol and Conventional Chemotherapeutic Drugs on Cancer Cells

Abstract

Objective: The objective of the present study was to evaluate synergistic growth inhibitory effect of a flavonol, kaempferol in combination with chemotherapeutic drugs doxorubicin or cisplatin. Methods:The anti-proliferative activities of kaempferol, doxorubicin and cisplatin on human colorectal cancer cells (HCT-15) and human breast cancer (MDA MB 231) were analyzed by 3-(4,5-dimehylthiaol-2-yl)-2,5-diphenyltetraolium bromide (MTT) assay. Further, combinational studies were performed in both the cell lines to evaluate the interaction of drugs with kaempferol. The combination index (CI) method was used to assess the synergism of kaempferol with doxorubicin or cisplatin. Finally, morphological alterations associated with apoptosis were examined under fluorescent microscope.Results: All compounds showed dose-dependent growth inhibition in both HCT-15 and MDA MB 231 cells. The phytochemical kaempferol showed fifty percent inhibitory concentrations (IC50) at 120±3.2 µg/ml and 64±1.2 µg/ml on HCT-15 and MDA MB 231 respectively. IC50 concentrations of doxorubicin and cisplatin on both the cell lines were achieved at 49.6±0.5 µg/ml, 25.4±2.9 µg/ml and 44±1.8 µg/ml, 40.6±0.8 µg/ml respectively. Further, in vitro therapeutic effect (IC50) of doxorubicin and cisplatin in terms of cell growth inhibition on HCT-15 cells were achieved at their onefifth (10±0.83 µg/ml) and half (10±1.34 µg/ml) concentrations respectively when they were combined with 30 µg/ml of kaempferol individually. Simultaneously, on MDA-MB 231 cell line, the IC50 concentrations were reduced to 18±1.22 µg/ml and 15±1.87 µg/ml respectively i Conclusion:The study reveals the prominent synergism between the phytochemical, kaempferol and chemotherapeutic drugs doxorubicin or cisplatin which helps in elevating the therapeutic efficacy of drugs.n combination with 32 µg/ml of kaempferol. The combinational index studies revealed the synergistic association of kaempferol with doxorubicin and cisplatin individually in each cell line. The fluorescence imaging studies strongly supported the synergistic association between kaempferol and doxorubicin or cisplatin by confirming significant apoptotic cell death in both the cell lines which was ~3 fold higher than each agent alone.

Febuxostat Modulates Oxidative and Apoptotic Pathways in Acute Doxorubicin‑induced Cardiotoxicity: An Experimental Animal Model Study

“…Different molecular mechanisms are involved in DIC which is multifactorial and complex, include direct DNA damage, formation of free reactive oxygen radicals, interference with DNA repair, alterations of cellular calcium homeostasis, mitochondria injury, lysosomal changes, and apoptosis [4,5]. The heart is particularly sensitive to the oxidative damage due to low levels of antioxidant enzymes, large density of mitochondrial, and high rate of oxygen consumption [6].…”

A systematic review of anti-cancer roles and mechanisms of kaempferol as a natural compound

“…The research presents the findings of kaempferol-cisplatin-doxorubicin combo investigations. The results demonstrated a substantial synergistic therapeutic benefit when doxorubicin or cisplatin was used in conjunction with kaempferol in HCT-15 and MDA-MB-231 cell lines [ 137 ].…”

Mitochondria-Targeting Small Molecules Effectively Prevent Cardiotoxicity Induced by Doxorubicin

“…Studies have shown that Kaempferol may participate in the ERK (extracellular signal-regulated kinase)-dependent MAPK pathway to reduce Dox-induced cardiac toxicity by inhibiting p53-mediated mitochondrial-dependent intrinsic apoptotic signaling [ 51 ]. A recent study showed that Kaempferol combined with Dox or cisplatin has a strong synergistic therapeutic effect on HCT-15 and MDA-MB-231 cells [ 50 ].…”