Adverse Effect of Luteolin on the Anticancer Ability of Oxaliplatin in HCT116 Human Colorectal Carcinoma Cells

Abstract

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers in the world. Intracellular oxidative stress by accumulation of reactive oxygen species (ROS) can cause redox imbalance that is associated with higher risks of cancer development. Dietary flavonoids activating a nuclear factor E2‐related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway have received a lot of attention due to their abilities to reduce oxidative stress by expressing antioxidant/phase II detoxifying enzymes. Hence, some cancer patients taking chemotherapeutic agents have been consuming flavonoid‐rich food, expecting their anticancer efficacies to be synergistically enhanced. However, careful consideration of possible undesired effects of flavonoid intake during chemotherapy is needed; flavonoids activating Nrf2/ARE signaling pathway could favor cancer cell survival by attenuating ROS‐induced oxidative stress elevated by anticancer agents. The purpose of the present study was to examine how luteolin would affect chemotherapeutic activity of oxaliplatin, a commonly used anticancer agent for colon cancer, in HCT116 p53+/+ cell line and its derivative HCT116 p53−/− cells. Results showed that luteolin increased ARE‐luciferase activity, decreased ROS level by Nrf2/ARE activation and subsequently stimulated proliferation of oxaliplatin‐treated colorectal cancer cells. In addition, oxaliplatin and a high dose of luteolin induced cell cycle arrest and apoptosis in a p53‐dependent manner, respectively. However, oxaliplatin‐induced cell cycle arrest was compromised by the high dose of luteolin in HCT116 p53+/+ cells. Moreover, the high dose of luteolin suppressed oxaliplatin‐induced p21 expression in HCT116 p53+/+ cells, but not in HCT116 p53−/− cells. Current observations indicate that a high dose of luteolin can negatively affect oxaliplatin‐based chemotherapy in a p53‐dependent fashion, suggesting that Nrf2‐activating flavonoids may interfere with chemotherapeutic efficacy of anticancer agents in colorectal cancer cells that carry functional p53 protein. Further studies about its in vivo impact of luteolin on oxaliplatin‐based chemotherapy are needed to ascertain current findings.Support or Funding InformationThis work was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT (MSIT), Republic of Korea.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Therapeutic Potential of Luteolin on Cancer

“…Interestingly, Jang et al, 2019 demonstrated that a high dose of Luteolin application negatively affected the oxaliplatin-based chemotherapy in a p53-dependent manner [ 52 ]. They suggested that the flavonoids with Nrf2-activating ability might interfere with the chemotherapeutic efficacy of anticancer agents in CRC cells with functional p53 protein [ 52 ].…”

“…Interestingly, Jang et al, 2019 demonstrated that a high dose of Luteolin application negatively affected the oxaliplatin-based chemotherapy in a p53-dependent manner [ 52 ]. They suggested that the flavonoids with Nrf2-activating ability might interfere with the chemotherapeutic efficacy of anticancer agents in CRC cells with functional p53 protein [ 52 ]. In a recent study, on the other hand, Aromokeye and Si, 2022 examined the synergistic inhibitory effect of the combination of Luteolin with another phytochemical, Curcumin, on colon cancer cells and found that the combination of Luteolin and Curcumin synergistically inhibited the proliferation of CL-188 and DLD-1 cells and the tumor growth in the CL-188 cells-derived xenograft mice [ 53 ].…”