Luteolin is a naturally-occurring polyphenolic compound that is known to have antioxidative and antitumor activities in vitro. This study aimed to examine the in vivo anticancer efficacy of luteolin in conjunction with oxaliplatin treatment using a colorectal carcinoma xenograft mouse model. HCT116 human colorectal carcinoma cells were subcutaneously implanted into BALB/c nude mice, followed by the intraperitoneal administration of luteolin at a dose of 50 mg/kg body weight (BW)/day with or without oxaliplatin at a dose of 10 mg/kg BW/day three times per week for a total of 3 weeks. The combined luteolin and oxaliplatin treatment resulted in the synergistic suppression of the growth of HCT116 xenograft tumors when compared to treatment with luteolin or oxaliplatin alone. In addition, the combined treatment significantly increased the expression of cleaved PARP and p53 in the xenograft tumors compared with the vehicle control, but only marginally affected the level of heme oxygenase-1 (HO-1). These results indicated that luteolin treatment retarded oxaliplatin-induced tumor growth by facilitating apoptotic cell death and inhibiting HO-1-mediated cytoprotection. Therefore, these findings suggest the synergistic potential of dietary luteolin in conjunction with conventional chemotherapy for the treatment of colorectal cancer.

Certain antioxidative flavonoids are known to activate nuclear factor E2-related factor 2 (Nrf2), a transcription factor that regulates cellular antioxidants and detoxifying response and is reportedly highly activated in many types of cancers. Few studies on the potential undesired effects of flavonoid intake during chemotherapy have been conducted, yet Nrf2 activators could favor cancer cell survival by attenuating chemotherapeutic efficiency. This study aimed to examine if luteolin, an Nrf2 activator, hinders chemotherapeutic activity of oxaliplatin, a potent anticancer agent for colorectal cancer, in HCT116 cells. Luteolin treatment strongly increased the transcriptional activity of the antioxidant response element in HCT116 cells and induced the protein expression of heme oxygenase-1, which were indicative of its Nrf2-inducing potential. Intriguingly, 25 μM luteolin reduced cell viability through apoptotic induction, which was intensified in p53-expressing cells while 1 μM oxaliplatin caused cell cycle arrest at G0/G1-phase via the p53/p21-dependent mechanism. Moreover, luteolin treatment was found to reduce oxaliplatin-treated p53-null cell viability and colony counts further, thereby demonstrating an additional effect of luteolin in the killing of human colorectal tumor HCT116 cells not expressing functional p53 protein. The findings suggest that luteolin can induce p53-mediated apoptosis regardless of oxaliplatin treatment and may eliminate oxaliplatin-resistant p53-null colorectal cells.

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.

Steamed soybean wastewater (SSW) is a commonly produced as a byproduct for manufacturing soybean food such as chonggukjang, doenjang, and natto, and may contain various water‐soluble and biologically beneficial constituents. In this study, we examined the general composition of SSW and additionally the protective effect against colorectal damage caused by dextran sodium sulfate (DSS) in adult male BALB/c mice. The moisture content in the SSW was 90.8±0.42%, crude protein 1.2±0.02%, crude lipid 0.13±0.01%, crude protein 0.85±0.05%, carbohydrate 7.02±0.32%. For animal study, the lyophilized SSW was dissolved in vehicle (consisting of 5% v/v ethanol, 5% v/v tween‐80, and 90% saline) and orally administered at a dose of 1 g/kg body weight on a daily basis for three weeks. Colorectal damage was induced by providing 3.5% (w/v) DSS in drinking water for the last nine days. We found that oral administration of SSW macroscopically and histologically improved DSS‐induced colorectal injury, reduced expressions of inflammatory cytokines and NF‐κB and its downstream proteins in the colorectal tissue, and decreased molecular markers of oxidative DNA damage (assessed by the plasm level of 8‐OHdG) and lipid peroxidation (measured by the MDA level in liver homogenate). These results suggest that dietary SSW can ameliorate colorectal damage by attenuation of inflammatory response.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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