wogonin and Colonic-Neoplasms

Colorectal cancers are one of the leading cancers worldwide and are known for their high potential for metastasis and resistance to therapy. The aim of this study was to investigate the effect of various combination therapies of irinotecan with melatonin, wogonin, and celastrol on drug-sensitive colon cancer cells (LOVO cell line) and doxorubicin-resistant colon cancer stem-like cells (LOVO/DX cell subline). Melatonin is a hormone synthesized in the pineal gland and is responsible for circadian rhythm. Wogonin and celastrol are natural compounds previously used in traditional Chinese medicine. Selected substances have immunomodulatory properties and anti-cancer potential. First, MTT and flow cytometric annexin-V apoptosis assays were performed to determine the cytotoxic effect and the induction of apoptosis. Then, the potential to inhibit cell migration was evaluated using a scratch test, and spheroid growth was measured. The results showed important cytotoxic effects of the drug combinations on both LOVO and LOVO/DX cells. All tested substances caused an increase in the percentage of apoptotic cells in the LOVO cell line and necrotic cells in the LOVO/DX cell subline. The strongest effect on the induction of cancer cell death was observed for the combination of irinotecan with celastrol (1.25 µM) or wogonin (50 µM) and for the combination of melatonin (2000 µM) with celastrol (1.25 µM) or wogonin (50 µM). Statistically significant improvements in the effect of combined therapy were found for the irinotecan (20 µM) and celastrol (1.25 µM) combination and irinotecan (20 µM) with wogonin (25 µM) in LOVO/DX cells. Minor additive effects of combined therapy were observed in LOVO cells. Inhibition of cell migration was seen in LOVO cells for all tested compounds, while only irinotecan (20 µM) and celastrol (1.25 µM) were able to inhibit LOVO/DX cell migration. Compared with single-drug therapy, a statistically significant inhibitory effect on cell migration was found for combinations of melatonin (2000 µM) with wogonin (25 µM) in LOVO/DX cells and irinotecan (5 µM) or melatonin (2000 µM) with wogonin (25 µM) in LOVO cells. Our research shows that adding melatonin, wogonin, or celastrol to standard irinotecan therapy may potentiate the anti-cancer effects of irinotecan alone in colon cancer treatment. Celastrol seems to have the greatest supporting therapy effect, especially for the treatment of aggressive types of colon cancer, by targeting cancer stem-like ce

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Colonic Neoplasms; Humans; Irinotecan; Melatonin

Wogonin is an effective component of

Topics: Animals; Colonic Neoplasms; Flavanones; HCT116 Cells; Hippo Signaling Pathway; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Xenograft Model Antitumor Assays

Hypoxia induced drug resistance is a major obstacle in the development of effective cancer therapy. In the present study, the reversal abilities of wogonin on the hypoxia resistance and the underlying mechanisms were discovered. MTT assay revealed that hypoxia increased maximal 1.71-, 2.08-, and 2.15-fold of IC50 toward paclitaxel, ADM, and DDP in human colon cancer cell lines HCT116, respectively. Furthermore, wogonin showed strong reversal potency in HCT116 cells in hypoxia and the RF reached 2.05. hypoxia-inducible factor-1α (HIF-1α) can activate the expression of target genes involved in glycolysis. Wogonin decreased the expression of glycolysis-related proteins (HKII, PDHK1, LDHA), glucose uptake, and lactate generation in a dose-dependent manner. Further, Western blot experiments exhibited that wogonin could down regulate HIF-1α expression and glycolysis through inhibiting PI3K/Akt signaling pathway, which might be the mechanism of reversal resistance of wogonin. Also, wogonin could inhibit the growth of transplantable tumors and the expression of HIF-1α, glycolysis-related proteins and PI3K/Akt in vivo. In summary, wogonin could be a good candidate for the development of new multidrug resistance (MDR) reversal agent and its reversal mechanism probably is due to the suppression of HIF-1α expression via inhibiting PI3K/Akt signaling pathway.

Topics: Animals; Apoptosis; Blotting, Western; Cell Proliferation; Colonic Neoplasms; Down-Regulation; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drugs, Chinese Herbal; Flavanones; Flow Cytometry; Glucose; Glycolysis; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Immunoenzyme Techniques; Lactates; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; Tumor Cells, Cultured