Synergistic effect of kaempferol and 5‑fluorouracil on the growth of colorectal cancer cells by regulating the PI3K/Akt signaling pathway

Abstract

combination chemotherapy with chemosensitizers can exert synergistic therapeutic effects, reduce toxicity, and delay the induction of drug resistance. in the present study, the antitumor effects were investigated, and the possible underlying mechanisms of kaempferol combined with 5-fluorouracil (5-Fu) in colorectal cancer cells were explored. HcT-8 or HcT-116 cells were treated with various concentrations of kaempferol and/or 5-Fu for the indicated time-points. an MTT assay was used to determine cell viability, whereas the synergistic effects were assessed by calculating the combination indices of kaempferol and 5-Fu. annexin V analysis and Hoechst staining were used to determine cell apoptosis. q-Pcr and western blotting were performed to determine the expression levels of Bax, Bcl-2, thymidylate synthase (TS), PTen, Pi3K, aKT, and p-aKT. The combination of kaempferol and 5-Fu was determined to be more effective in inhibiting cell viability than either of the agents alone. The inhibition of tumors in response to kaempferol and 5-Fu was associated with the reduction in proliferation ability and stimulation of apoptosis. The protein results indicated that kaempferol and 5-FU could significantly upregulate the expression levels of Bax and downregulate the expression levels of Bcl-2 and TS. Furthermore, the combination treatment greatly inhibited the activation of the Pi3K/akt pathway, suggesting the involvement of this pathway in the synergistic effects. The present study demonstrated that kaempferol has a synergistic effect with 5-Fu by inhibiting cell proliferation and inducing apoptosis in colorectal cancer cells via suppression of TS or attenuation of p-akt activation. The combination of kaempferol and 5-Fu may be used as an effective therapeutic strategy for colorectal cancer.

Anti-Cancer Potential of Cannabinoids, Terpenes, and Flavonoids Present in Cannabis

“…Kaempferol + TRAIL induced apoptosis [350]. Kaempferol + 5-fluorouracil had synergistic anti-proliferative effects and re-sensitized resistant cells to chemotherapeutic agents [341,351].…”

“…Hassanzadeh et al [350] found that co-treatment of lymphoblastic leukemia (MOLT-4) cells with TRAIL and kaempferol was able to induce apoptosis by inhibiting the expression of anti-apoptotic proteins and up-regulation of death receptors 4 and 5, and they suggested that this co-treatment could be used as a potential solution to overcome resistance to TRAIL in cancers. Li et al [351] looked at the potential of combining 5-fluorouracil (5-FU) with kaempferol in colorectal cancer. They found that the combination of 5-FU and kaempferol was superior at inhibiting cell viability than either agent alone, and the anti-cancer effects were mediated through reduction in cell proliferation and induction of apoptosis.…”

Kaempferol ameliorates Cisplatin induced nephrotoxicity by modulating oxidative stress, inflammation and apoptosis via ERK and NF-κB pathways

“…Kaempferol exerts number of pharmacological properties such as reducing oxidative stress, anticancer and anti-inflammatory (Kampkotter et al 2007;Park et al 2009;Nguyen et al 2003). Kaempferol has been reported to show inhibitory action on PI3K/Akt pathway and cyclooxygenase-2 (Li et al 2019;Kang et al 2018). In a report recently Kaempferol was found to inhibit the activation of NF-κB (Kadioglu et al 2015).…”

Investigating the Multitarget Mechanism of Traditional Chinese Medicine Prescription for Cancer‐Related Pain by Using Network Pharmacology and Molecular Docking Approach

“…Moreover, they also have a strong inhibitory effect on inflammation through the inhibition of lipoxygenase and cyclooxygenase pathways. Among them, kaempferol has been used as a chemosensitizer in clinical research and has the potential of reducing toxicity and enhancing efficacy [ 25 ].…”