Chemomodulatory Effect of the Marine-Derived Metabolite "Terrein" on the Anticancer Properties of Gemcitabine in Colorectal Cancer Cells.

BACKGROUND: Terrein (Terr) is a bioactive marine secondary metabolite that possesses antiproliferative/cytotoxic properties by interrupting various molecular pathways. Gemcitabine (GCB) is an anticancer drug used to treat several types of tumors such as colorectal cancer; however, it suffers from tumor cell resistance, and therefore, treatment failure. METHODS: The potential anticancer properties of terrein, its antiproliferative effects, and its chemomodulatory effects on GCB were assessed against various colorectal cancer cell lines (HCT-116, HT-29, and SW620) under normoxic and hypoxic (pO2 ≤ 1%) conditions. Further analysis via flow cytometry was carried out in addition to quantitative gene expression and 1HNMR metabolomic analysis. RESULTS: In normoxia, the effect of the combination treatment (GCB + Terr) was synergistic in HCT-116 and SW620 cell lines. In HT-29, the effect was antagonistic when the cells were treated with (GCB + Terr) under both normoxic and hypoxic conditions. The combination treatment was found to induce apoptosis in HCT-116 and SW620. Metabolomic analysis revealed that the change in oxygen levels significantly affected extracellular amino acid metabolite profiling. CONCLUSIONS: Terrein influenced GCB's anti-colorectal cancer properties which are reflected in different aspects such as cytotoxicity, cell cycle progression, apoptosis, autophagy, and intra-tumoral metabolism under normoxic and hypoxic conditions.

Dual action of epigallocatechin-3-gallate in virus-induced cell Injury.

BACKGROUND: Viral infections cause damage and long-term injury to infected human tissues, demanding therapy with antiviral and wound healing medications. Consequently, safe phytochemical molecules that may control viral infections with an ability to provide wound healing to viral-induced tissue injuries, either topically or systemically, are advantageous. Herein, we hypothesized that epigallocatechin-3-gallate (EGCG), the most abundant polyphenol in green tea, might be effective as a wound healing, antiviral, and antifibrotic therapy. RESULTS: The antiviral activities of EGCG against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Herpes simplex virus type 2 (HSV-2) as well as its wound healing activities against different monolayer tissue (continuous and primary) systems were investigated. Consider its possible wound-healing advantages as well. To determine the safe concentrations of EGCG in green monkey kidney (Vero) and Vero-E6 cell lines, MTT assay was performed and showed high CC50 values of 405.1 and 322.9 µM, respectively. The antiviral activities of EGCG against SARS-CoV-2 and HSV-2, measured as half-maximal concentration 50 (IC50) concentrations, were 36.28 and 59.88 µM, respectively. These results confirm that the EGCG has remarkable viral inhibitory activities and could successfully suppress the replication of SARS-CoV-2 and HSV-2 in vitro with acceptable selectivity indices (SI) of 11.16 and 5.39, respectively. In parallel, the EGCG exhibits significant and dose/time-dependent anti-migration effects in human breast cancer cells (MCF-7), its resistant variation (MCF-7adr), and human skin fibroblast (HSF) indicating their potential to heal injuries in different internal and topical mammalian systems. CONCLUSIONS: The EGCG has proven to be an efficient antiviral against SARS-CoV-2 and HSV-2, as well as a wound-healing phytochemical. We assume that EGCG may be a promising option for slowing the course of acute cellular damage induced by systemic (Coronavirus Disease 2019 (COVID-19)) or topical (HSV-2) viral infections.

Novel application of multicellular layers culture for in situ evaluation of cytotoxicity and penetration of paclitaxel.

Limited drug penetration into tumor tissue is one of the major factors causing clinical drug resistance in human solid tumors. The multicellular layers (MCL) of human cancer cells have been successfully used to study tissue pharmacokinetics of anticancer drugs. The purpose of this study was to develop a direct and simple method to evaluate vitality changes in situ within MCL using calcein-AM. Human colorectal (DLD-1, HT-29) and bladder (HT-1376, J-82) cancer cells were grown in Transwell inserts to form MCL and subjected to paclitaxel exposure. The drug distribution was evaluated using paclitaxel-rhodamine. Photonic attenuation and limited penetration of calcein-AM prevented cellular vitality evaluation on optical sections under confocal microscopy in DLD-1 MCL. However, direct measurement of the fluorescence intensity on frozen sections of MCL allowed successful vitality assessment in more than 80% depth for HT-29 and J-82 MCL and in the upper 40% depth for DLD-1 and HT-1376 MCL. The penetration of paclitaxel-rhodamine was greater in HT-29 than DLD-1 and its distribution pattern was correlated to the spatial profile of vitality deterioration in both MCL, suggesting that tissue penetration may be an important determinant of drug effect in tumors. In conclusion, a novel method for vitality evaluation in situ within MCL was developed using calcein-AM. This method may provide clinically relevant data regarding the spatial pharmacodynamics of anticancer agents within avascular regions of solid tumors.