GDF15 negatively regulates chemosensitivity via TGFBR2-AKT pathway-dependent metabolism in esophageal squamous cell carcinoma / 医学前沿

Treating patients with esophageal squamous cell carcinoma (ESCC) is challenging due to the high chemoresistance. Growth differentiation factor 15 (GDF15) is crucial in the development of various types of tumors and negatively related to the prognosis of ESCC patients according to our previous research. In this study, the link between GDF15 and chemotherapy resistance in ESCC was further explored. The relationship between GDF15 and the chemotherapy response was investigated through in vitro and in vivo studies. ESCC patients with high levels of GDF15 expression showed an inferior chemotherapeutic response. GDF15 improved the tolerance of ESCC cell lines to low-dose cisplatin by regulating AKT phosphorylation via TGFBR2. Through an in vivo study, we further validated that the anti-GDF15 antibody improved the tumor inhibition effect of cisplatin. Metabolomics showed that GDF15 could alter cellular metabolism and enhance the expression of UGT1A. AKT and TGFBR2 inhibition resulted in the reversal of the GDF15-induced expression of UGT1A, indicating that TGFBR2-AKT pathway-dependent metabolic pathways were involved in the resistance of ESCC cells to cisplatin. The present investigation suggests that a high level of GDF15 expression leads to ESCC chemoresistance and that GDF15 can be targeted during chemotherapy, resulting in beneficial therapeutic outcomes.

Beneficial effects of glucan against cisplatin side effects on the nervous system in rats 1

ABSTRACT PURPOSE: To investigate the protective effect of Bg on cisplatin (CP)-induced neurotoxicity in rats. METHODS: Twenty eight rats were randomly distributed into four groups. The first group was kept as a control. In the second group, CP was given at the single dose of 7 mg/kg intraperitoneally. In the third group, βg was orally administered at the dose of 50 mg/kg/day for 14 days. In the fourth group, CP and βg were given together at the same doses. RESULTS: CP treatment caused significant oxidative damage via induction of lipid peroxidation and reductions antioxidant defense system potency in the brain tissue. In addition, histopathological damage increased with CP treatment. On the other hand, βg treatment largely prevented oxidative and histopathological negative effects of CP. CONCLUSIONS: Cisplatin has severe neurotoxic effects in rats and βg supplementation has significant beneficial effects against CP toxicity depending on its antioxidant properties. Thus, it appears that βg might be useful against CP toxicity in patients with cancer in terms of nervous system.

Nefrotoxicidade aguda da cisplatina: mecanismos moleculares / Acute nephrotoxicity of cisplatin: molecular mechanisms

As drogas nefrotóxicas são responsáveis por aproximadamente 20% dos episódios de IRA em pacientes internados e ambulatoriais. A nefrotoxicidade pela cisplatina é um dos principais fatores limitantes em até 20% dos pacientes que recebem a droga, ocasionando lesões em células do epitélio tubular renal. A toxicidade da cisplatina é determinada pelo tecido-alvo e acúmulo nas células, além da interação com diversas estruturas subcelulares e com macromoléculas. A cisplatina se acumula e interfere com o funcionamento de diferentes organelas, tais como: mitocôndrias, lisossomas, retículo endoplasmático, núcleo e membrana celular, gerando inflamação e morte celular. Esta revisão tem como objetivo definir as bases fisiopatológicas e bioquímicas da nefrotoxicidade da cisplatina, revisando os principais mecanismos moleculares que levam à toxicidade tubular da cisplatina.

The nephrotoxic drugs have been responsible for about 20% of AKI episodes in inpatients and outpatients. The cisplatin nephrotoxicity is a major limiting factors in 20% of patients who have received the drug, triggering injuries in renal tubular epithelialcells. Cisplatin toxicity is determined by the target tissue and cells accumulation besides the interaction with various subcellular structures and macromolecules. Cisplatin accumulates and interferes with the functioning of different organelles such as mitochondria, lysosomes, endoplasmic reticulum, nuclei and cell membranes, causing inflammation and cell death. This review aims to define the pathophysiology and biochemistry of the cisplatin nephrotoxicity, reviewing the main molecular mechanisms that lead to tubular cisplatin toxicity.

Suppression of apoptosis leads to cisplatin resistance in V79 cells subjected to chronic oxidative stress.

We derived V79C cells from V79 cell line through chronic oxidative stress by H2O2. These cells demonstrated transformation-like stable changes. Our objective was to see how V79C cells would respond to cisplatin treatment and also to understand the mechanism of cisplatin-resistance, because resistance towards various chemotherapeutic agents is major cause of concern in cancer therapeutics. The sensitivity to cisplatin in these cells was observed by comparing the viability with that of parental V79 cells from colonogenic assay. The role of apoptotic death was investigated microscopically by Hoechst staining and from nucleosomal ladder formation in agarose gel. Release of cytochrome c from the mitochondria was determined by Western blotting. Caspase 9 and caspase 3 activities were estimated through fluorimetric assay. We found that V79C cells exhibited lower sensitivity towards killing by cisplatin through suppression of apoptotic cell death. Quantifying the release of cytochrome c in the cytoplasm and assay of caspase 9 and caspase 3 activities revealed that cisplatin resistance was due to inhibition of caspase-dependent apoptotic death pathways. These findings may aid in understanding the mechanism of cisplatin resistance in tumors arising from oxidative stress. Exogenous caspases may facilitate apoptotic death to sensitize such resistant cells.