Rapamycin and fructose-1,6-bisphosphate reduce the HEPG2 cell proliferation via increase of free radicals and apoptosis

Abstract

Hepatocellular carcinoma is the most prevalent type of tumor among primary tumors affecting the liver. Rapamycin is currently used as a basis for chemotherapy in the treatment of cancers, including the liver. Because it shows several adverse effects, minimizing these effects without compromising efficacy is important. In this sense other drugs may be used concomitantly. One of these drugs is fructose-1,6-bisphosphate (FBP), which has shown therapeutic effect in various pathological situations, having antioxidant and anti-inflammatory proprieties. The objective of the present study was to evaluate the activity of rapamycin in combination with the FBP in HepG2 cell proliferation and the mechanisms involved. HepG2 cells were analyzed after 72 h of treatment with both drugs. Cell proliferation, cytotoxicity, cytokines, apoptosis, senescence, autophagy and oxidative stress were accessed. Ιt was demonstrated that the combination is more efficient than the single use of substances, because subtherapeutic doses of rapamycin, when associated to FBP become effective, reducing cell proliferation, through a significant increase in the production of tiobarbituric acid reactive substances (TBARS), suggesting that this might be the cause of death by apoptosis. According to these results, we believe that the association of both drugs may be a promising choice for the treatment of hepatocarcinoma.

Fructose‐1,6‐bisphosphate induces generation of reactive oxygen species and activation of p53‐dependent cell death in human endometrial cancer cells

“…Suggestive of autophagy induction, the formation of the autophagosomes induced by F1,6BP treatment in EC cells corroborates with previous studies in cancer cells treated with the same molecule (Da Silva et al, 2016). This is the first report of F1,6BP-mediated autophagy in Ishikawa cells as far as we know.…”

“…Our results showed an increase of ROS levels generated by treatment with F1,6 BP in human EC cells (Ishikawa). Studies have also identified that cancer cells may become vulnerable to PCD in response to exogenous F1,6 BP administration due to the induction of increased ROS levels (Da Silva et al, 2016; Li, Wei, Shen, & Hu, 2014; Lu, Yu, & Zhu, 2014).…”

Fructose-1,6-bisphosphate prevents pulmonary fibrosis by regulating extracellular matrix deposition and inducing phenotype reversal of lung myofibroblasts

“…Others showed that FBP induced oxidative stress in hepatic carcinoma cells, which caused an inhibition in proliferation, and this effect was suppressed when these cells were treated with anti-oxidants, such as N-acetyl-l-cysteine or catalase [12]. In contrast, using the same cell line, HepG2, FBP-treatment led to cell senescence, an increase in catalase activity [10] and a decrease in thiobarbituric acid reactive substances, which is a lipid peroxidation product and an indirect measure of radical oxygen species (ROS) [57]. Regardless of this discrepancy, there is a strong body of evidence suggesting that FBP has anti-oxidant properties [13] and, in the present study, FBP was able to increase expression of an antioxidant enzyme, SOD1, in FLF.…”

The Role of Tumor Microenvironment in Chemoresistance: To Survive, Keep Your Enemies Closer

“…Hypoxia can result in the activation of genes associated with angiogenesis and cell survival [ 146 , 147 , 148 ]. Many chemotherapeutic drugs cause DNA damage through generating free radicals [ 149 , 150 , 151 ]. Without oxygen however, the cytotoxicity of several chemotherapeutic drugs whose activity depends on generating free radicals is reduced.…”