3,3',5,5'-Tetramethoxybiphenyl-4,4'diol triggers oxidative stress, metabolic changes, and apoptosis-like process by reducing the PI3K/AKT/NF-κB pathway in the NCI-H460 lung cancer cell line.

Lung cancer is one of the leading causes of cancer-related deaths in men and women worldwide. Current treatments have limited efficacy, cause significant side effects, and cells can develop drug resistance. New therapeutic strategies are needed to discover alternative anticancer agents with high efficacy and low-toxicity. TMBP, a biphenyl obtained by laccase-biotransformation of 2,6-dimethoxyphenol, possesses antitumor activity against A549 adenocarcinoma cells. Without causing damage to sheep erythrocytes and mouse peritoneal macrophages of BALB/c mice. In addition to being classified as a good oral drug according to in-silico studies. This study evaluated the in-vitro cytotoxic effect of TMBP on lung-cancer cell-line NCI-H460 and reports mechanisms on immunomodulation and cell death. TMBP treatment (12.5-200 µM) inhibited cell proliferation at 24, 48, and 72 h. After 24-h treatment, TMBP at IC50 (154 µM) induced various morphological and ultrastructural changes in NCI-H460, reduced migration and immunofluorescence staining of N-cadherin and ß-catenin, induced increased reactive oxygen species and nitric oxide with reduced superoxide radical-anion, increased superoxide dismutase activity and reduced glutathione reductase. Treatment also caused metabolic stress, reduced glucose-uptake, intracellular lactate dehydrogenase and lactate levels, mitochondrial depolarization, increased lipid droplets, and autophagic vacuoles. TMBP induced cell-cycle arrest in the G2/M phase, death by apoptosis, increased caspase-3/7, and reduced STAT-3 immunofluorescence staining. The anticancer effect was accompanied by decreasing PI3K, AKT, ARG-1, and NF-κB levels, and increasing iNOS. These results suggest its potential as a candidate for use in future lung anticancer drug design studies.

3,3',5,5'-tetramethoxybiphenyl-4,4'diol induces cell cycle arrest in G2/M phase and apoptosis in human non-small cell lung cancer A549 cells.

Lung cancer is one of the leading causes of cancer-related death worldwide. It has aggressive manifestation, high ability to promote metastasis and late diagnosis. In the present study, we investigated the cytotoxic effect of 3,3',5,5'-tetramethoxybiphenyl-4,4'diol (TMBP), against the A549 human non-small cell lung carcinoma lineage. The A549 cell line was treated for 72h with TMBP (12.5-200 µM) with and subsequently defined the 50% inhibitory concentration (148 µM ± 0.05), from which tests were performed to determine the viability, volume, and regulation of the cell cycle. Finally, we investigated the death mechanisms involved in the action of the treatments by flow cytometry and fluorimetry. The TMBP-treatment of primary cells, peritoneal macrophages, and sheep erythrocytes did not reduce the viability of these cells. On the other hand, TMBP was able to reduce the viability of the investigated cell line, by cytotoxic action and to promote the reduction of cell size. Subsequently, we found that TMBP treatment was able to increase the production of reactive oxygen species, cause mitochondrial depolarization, induce cell cycle arrest in G2/M phase and lead to death by direct apoptosis. Thus, this study revealed that TMBP could be a promising candidate for the development of antitumor drugs targeting lung cancer.