Drug Resistance and Endoplasmic Reticulum Stress in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide. It is usually diagnosed in an advanced stage and is characterized by a high intrinsic drug resistance, leading to limited chemotherapeutic efficacy and relapse after treatment. There is therefore a vast need for understanding underlying mechanisms that contribute to drug resistance and for developing therapeutic strategies that would overcome this. The rapid proliferation of tumor cells, in combination with a highly inflammatory microenvironment, causes a chronic increase of protein synthesis in different hepatic cell populations. This leads to an intensified demand of protein folding, which inevitably causes an accumulation of misfolded or unfolded proteins in the lumen of the endoplasmic reticulum (ER). This process is called ER stress and triggers the unfolded protein response (UPR) in order to restore protein synthesis or—in the case of severe or prolonged ER stress—to induce cell death. Interestingly, the three different arms of the ER stress signaling pathways have been shown to drive chemoresistance in several tumors and could therefore form a promising therapeutic target. This review provides an overview of how ER stress and activation of the UPR contributes to drug resistance in HCC.

Elucidation of Structure–Activity Relationships in Indolobenzazepine-Derived Ligands and Their Copper(II) Complexes: the Role of Key Structural Components and Insight into the Mechanism of Action

“…H 9 ), 4.28 (d, J = 3.0 Hz, 2H, H 5 ) 2.50 (s, 3H, H 22 ). 13 [3,2-d]benzazepin(6H)one (F) (150 mg, 0.43 mmol) in methanol (6.5 mL) in a 10 mL Schlenk tube was deoxygenated by bubbling argon through the solution for 10 min. 2-Acetylpyridine (48.2 μL, 1 equiv) was added, and the mixture was stirred at 75 °C overnight.…”

“…The yellow product was precipitated by addition of diethyl ether (6.5 mL) Electrospray ionization (ESI) mass spectra were recorded on a Bruker amaZon SL ion trap spectrometer or a Bruker maXis UHR-TOF mass spectrometer in the positive mode by direct infusion at the Mass Spectrometry Centre of the University of Vienna. One-and twodimensional 1 H and 13 C NMR spectra were recorded on a Bruker AV Neo 500 or AV III 600 spectrometer at 25 °C. For 1 H and 13 C NMR spectra, the solvent residual peak was taken as the internal reference.…”

“…One-and twodimensional 1 H and 13 C NMR spectra were recorded on a Bruker AV Neo 500 or AV III 600 spectrometer at 25 °C. For 1 H and 13 C NMR spectra, the solvent residual peak was taken as the internal reference. UV−vis spectra were recorded on an Agilent 8453 UV−visible spectroscopy system at 25 °C.…”

“…The search for effective metal-based anticancer drugs with new mechanisms of action to reduce side effects and overcome acquired drug resistance continues to attract the attention of researchers. − Various mechanisms of drug resistance in cancer cells were shown to be intertwined with their ability to adapt to the proteotoxic stress . Therefore, one promising direction is the development of anticancer drug candidates inducing severe endoplasmic reticulum (ER) stress, resulting in the inability of cancer cells to restore protein homeostasis and cancer cell death. − ER is the largest organelle in eukaryotic cells for calcium storage, lipid biosynthesis, entry, folding, and assembly of proteins for a secretory pathway .…”

Ion-selective electrode-based potentiometric immunoassays for the quantitative monitoring of alpha-fetoprotein by coupling rolling cycle amplification with silver nanoclusters

“…Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China with a high incidence in the southeast coastal areas, which is caused by hepatocytes or bile duct epithelial cells. 1 The median age of hepatocellular carcinoma patients in China is 40 to 50 years old, and it is more common in men than in women. 2 Hepatocellular carcinoma has occult morbidity, no clinical signs and symptoms in the early stage, and has entered the late stage when it is found.…”