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.
Quercetin is an antioxidant phytochemical which belongs to the natural flavonoids group. Recently, the compound has been reported to inhibit glutathione reductase responsible for replenishing reduced forms of glutathione and thus leads to glutathione depletion, triggering cell death. In this study, we examined if quercetin sensitizes tumors to oxaliplatin by inhibiting glutathione reductase activity in human colorectal cancer cells, and thereby facilitates apoptotic cell death. A combined treatment with quercetin and oxaliplatin was found to synergistically inhibit glutathione reductase activity, lower intracellular glutathione level, increase reactive oxygen species production, and reduce cell viability, compared to treatment with oxaliplatin alone in human colorectal HCT116 cancer cells. Furthermore, the incorporation of sulforaphane, recognized for its ability to scavenge glutathione, in combination with quercetin and oxaliplatin, substantially suppressed tumor growth in an HCT116 xenograft mouse model. These findings suggest that the depletion of intracellular glutathione by quercetin and sulforaphane could strengthen the anti-cancer efficacy of oxaliplatin.
Alzheimer’s disease (AD), a neurodegenerative disorder, has been known to be mostly commonly diagnosed in people over the age of 65. However, there is no drug that can cure AD. This study aimed to investigate if wasp venom (WV) can mitigate phenotypes of AD using a 5xFAD transgenic mouse model. The mice were administered intraperitoneally with WV obtained from Vespa velutina at a concentration of 250 or 400 μg/kg body weight (BW) once a week for a total of 14 weeks. WV treatment was shown to alleviate memory impairments in 5xFAD mice in behavioral tasks, including passive avoidance, Y‐maze and Morris water maze tests. In addition, we found that WV treatment decreased the level of 8‐hydroxy‐2′‐deoxyguanosine, a biomarker of oxidative DNA damage, in mouse plasma and the level of malondialdehyde, an indicative of lipid peroxidation, in liver and cerebral cortex, indicating that WV prevents oxidative damage. In particular, WV treatment increased expression of antioxidant‐associated proteins, a nuclear factor erythroid‐derived 2‐related factor 2 (Nrf2) and heme oxygenase‐1 (HO‐1), in the cerebral cortex and decreased inflammation‐associated protein, cyclooxygenase‐2 (COX‐2), amyloid beta (Aβ) plaque‐associated proteins, C‐terminal fragment (C99), and beta‐site amyloid precursor protein cleaving enzyme 1 (BACE1, β‐secretase) in the hippocampal tissue homogenates. Furthermore, we confirmed that WV treatment reduced the accumulation of Aβ plaque in the hippocampal area via thioflavin S staining. Taken together, these findings suggest that WV could ameliorate AD symptoms and delay AD onset and progression.
Sulforaphane (SFN), a sulfur‐containing compound that belongs to the isothiocyanate class of dietary phytochemicals found in cruciferous vegetables, has been known to cause a hormetic effect on cancer cell growth. We previously reported that SFN at low doses stimulated proliferation of HCT116 human colorectal carcinoma cells through Nrf2 activation in vitro and in vivo. Recently, we discovered that brusatol, a nuclear factor erythroid 2‐related factor 2 (Nrf2) inhibitor, significantly suppressed the SFN‐induced proliferation of HCT116 cells. Therefore, we hypothesized that SFN‐induced proliferation of HCT116 cells is mediated by an Nrf2 downstream gene(s). Transcriptomic profiling revealed a set of differentially expressed genes (DEGs) involved in glutathione (GSH) metabolism as compared between wildtype (WT) and Nrf2 knockout (KO) HCT116 cells treated with or without SFN. In particular, we found that glutamate‐cysteine ligase catalytic subunit (GCLC) was highly elevated in SFN‐treated WT HCT116 cells among the DEGs, but not in SFN‐treated Nrf2 KO HCT116 cells. To confirm if upregulation of γ‐glutamate‐cysteine ligase (γ‐GCL) is associated with SFN‐induced proliferation of HCT116 cells, inhibiting γ‐GCL by buthionine sulfoximine (BSO, a selective γ‐GCL inhibitor) and silencing GCLC by short hairpin RNA (shRNA) were carried out. The results showed that SFN‐induced proliferation of HCT116 cells was significantly reduced by γ‐GCL inhibition and abolished by GCLC knockdown. Furthermore, we confirmed that BSO suppressed SFN‐induced tumor growth of WT HCT116 xenograft mice and the tumor growth was not stimulated in both Nrf2 KO and GCLC shRNA HCT16 xenograft mice by SFN at a low dose. Collectively, these findings indicate that upregulation of GCLC‐dependent GSH biosynthesis by SFN promotes proliferation of HCT116 cells and thus GCL could be a potential target for chemotherapy.
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