Novel molecular targets in hepatocellular carcinoma

Zhu

Biomedical Chromatography

et al. 2022

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the second most common cause of cancer deaths. This study aimed to explore the inhibitory effect and mechanism of Aidi injection (ADI) combined with doxorubicin (DOX) in HCC treatment. The drug concentrations in the combined therapy was determined by investigating the effect of various concentrations of ADI and DOX on the viability of H22 cells. The combination index was also calculated. A metabolomic strategy based on a ultrahigh-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) platform was established to analyze the metabolites. As a result, the combination index values were less than 1, indicating that the combination of ADI and DOX exerted a synergistic effect on HCC treatment. The combination of 40‰ ADI and 1 μmol/l DOX had the strongest inhibitory effect and was used for subsequent metabolomic analysis. A total of 19 metabolic markers were obtained in metabolomic analysis, including amino acids (L-glutamic acid, L-arginine and L-tyrosine), organic acids (succinic acid and citric acid), adenosine and hypoxanthine. Compared with the treatment using DOX or ADI alone, the combined therapy further regulated the levels of metabolic markers in HCC, which may be the reason for the synergistic effect. Seven metabolic pathways were significantly enriched, including phenylalanine, tyrosine and tryptophan biosynthesis, D-glutamine and D-glutamate metabolism, alanine, aspartate and glutamate metabolism, phenylalanine metabolism, arginine biosynthesis, the tricarboxylic acid cycle and purine metabolism. These findings demonstrated that ADI combined with DOX can effectively inhibit the viability of H22 cells, which may exert a synergistic antitumor effect by balancing the metabolism of amino acids and energy-related substances.

Section: Discussionmentioning

confidence: 99%

Cell metabolomics study on synergistic anti‐hepatocellular carcinoma effect of Aidi injection combined with doxorubicin

Zhu

Biomedical Chromatography

et al. 2022

“…The molecularly targeted agents represented by sorafenib remain the first-line choice to treat advanced HCC ( 49 – 51 ). Although some clinical trials have shown that the oral administration of sorafenib (as NATCO) could improve the survival of patients, the side effects in these trials cannot be ignored ( 52 ).…”

Section: Discussionmentioning

confidence: 99%

Novel Microcrystal Formulations of Sorafenib Facilitate a Long-Acting Antitumor Effect and Relieve Treatment Side Effects as Observed With Fundus Microcirculation Imaging

Zhao³

et al. 2021

Front. Oncol.

The tyrosine kinase inhibitors (TKIs), including sorafenib, remain one first-line antitumor treatment strategy for advanced hepatocellular carcinoma (HCC). However, many problems exist with the current orally administered TKIs, creating a heavy medical burden and causing severe side effects. In this work, we prepared a novel microcrystalline formulation of sorafenib that not only achieved sustainable release and long action in HCC tumors but also relieved side effects, as demonstrated by fundus microcirculation imaging. The larger the size of the microcrystalline formulation of sorafenib particle, the slower the release rates of sorafenib from the tumor tissues. The microcrystalline formulation of sorafenib with the largest particle size was named as Sor-MS. One intratumor injection (once administration) of Sor-MS, but not Sor-Sol (the solution formulation of sorafenib as a control), could slow the release of sorafenib in HCC tumor tissues and in turn inhibited the in vivo proliferation of HCC or the expression of EMT/pro-survival–related factors in a long-acting manner. Moreover, compared with oral administration, one intratumor injection of Sor-MS not only facilitated a long-acting antitumor effect but also relieved side effects of sorafenib, avoiding damage to the capillary network of the eye fundus, as evidenced by fundus microcirculation imaging. Therefore, preparing sorafenib as a novel microcrystal formulation could facilitate a long-acting antitumor effect and relieve drug-related side effects.

“…Despite recent advances in HCC treatment, only 18% of patients survive more than 5 years after initial diagnosis, a percentage significantly lower compared to other cancer types [ 402 ]. The poor prognosis is usually attributed to late diagnosis and lack of response to adjuvant therapies [ 403 ].…”

Section: Discussionmentioning

confidence: 99%

In Vivo and In Vitro Models of Hepatocellular Carcinoma: Current Strategies for Translational Modeling

Romualdo

Leroy

Costa

et al. 2021

Cancers

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third leading cause of cancer-related death globally. HCC is a complex multistep disease and usually emerges in the setting of chronic liver diseases. The molecular pathogenesis of HCC varies according to the etiology, mainly caused by chronic hepatitis B and C virus infections, chronic alcohol consumption, aflatoxin-contaminated food, and non-alcoholic fatty liver disease associated with metabolic syndrome or diabetes mellitus. The establishment of HCC models has become essential for both basic and translational research to improve our understanding of the pathophysiology and unravel new molecular drivers of this disease. The ideal model should recapitulate key events observed during hepatocarcinogenesis and HCC progression in view of establishing effective diagnostic and therapeutic strategies to be translated into clinical practice. Despite considerable efforts currently devoted to liver cancer research, only a few anti-HCC drugs are available, and patient prognosis and survival are still poor. The present paper provides a state-of-the-art overview of in vivo and in vitro models used for translational modeling of HCC with a specific focus on their key molecular hallmarks.