Anti-tumoral activity of single and combined regorafenib treatments in preclinical models of liver and gastrointestinal cancers

Fondevila, Flavia; Méndez-Blanco, Carolina; Fernández-Palanca, Paula; González‐Gallego, Javier; Mauriz, José L.

doi:10.1038/s12276-019-0308-1

Cited by 60 publications

(55 citation statements)

References 88 publications

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“…1–5 mM melatonin co-administration promotes sorafenib-induced apoptosis through synergistic activation of JNK/c-jun pathway and caspase-3 in a dose-dependent manner in HuH7 HCC cells [ 44 ]. Moreover, as indicated above, 50 µM melatonin also increased regorafenib-induced apoptosis; this molecule inhibits multiple kinases and has been approved for patients with sorafenib-resistant HCC [ 70 ]. It has been noted that melatonin can enhance the regorafenib-associated Sirt3 upregulation, promoting mitochondrial dysfunction with mitochondrial depolarization and induction of apoptosis in SMMC-7721 HCC cells [ 60 ].…”

Section: Resultsmentioning

confidence: 99%

Melatonin as an Antitumor Agent against Liver Cancer: An Updated Systematic Review

et al. 2021

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Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine with antioxidant, chronobiotic and anti-inflammatory properties; reduced levels of this hormone are associated with higher risk of cancer. Several beneficial effects of melatonin have been described in a broad number of tumors, including liver cancers. In this work we systematically reviewed the publications of the last 15 years that assessed the underlying mechanisms of melatonin activities against liver cancers, and its role as coadjuvant in the treatment of these tumors. Literature research was performed employing PubMed, Scopus and Web of Science (WOS) databases and, after screening, 51 articles were included. Results from the selected studies denoted the useful actions of melatonin in preventing carcinogenesis and as a promising treatment option for the primary liver tumors hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), either alone or in combination with other compounds. Different processes were modulated by the indole, such as inhibition of oxidative stress, proliferation, angiogenesis and invasion, promotion of immune system response, cell cycle arrest and apoptosis, as well as recovery of circadian rhythms and autophagy modulation. Taken together, the present systematic review highlights the evidence that document the potential role of melatonin in improving the landscape of liver tumor treatment.

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Section: Resultsmentioning

confidence: 99%

Melatonin as an Antitumor Agent against Liver Cancer: An Updated Systematic Review

et al. 2021

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“…It is also a multi-kinase inhibitor targeting STAT3, nuclear factor-κB (NF-κB) and other HCC-related factors. [138][139][140] The RESORCE trial showed that regorafenib could improve OS significantly compared with placebo (10.6 months versus 7.8 months) in HCC patients progressing on sorafenib treatment. An exploratory analyses from the RESORCE trial reached the conclusion that the sequence of sorafenib followed by regorafenib for HCC may extend survival compared with sorafenib followed by placebo (26 months versus 19 months).…”

Section: Perspectivesmentioning

confidence: 99%

Is the era of sorafenib over? A review of the literature

Fan

Wei

2020

Ther Adv Med Oncol

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Hepatocellular carcinoma (HCC) is one of the most severe diseases worldwide. For the different stages of HCC, there are different clinical treatment strategies, such as surgical therapy for the early stage, and transarterial chemoembolization (TACE) and selective internal radiation therapy (SIRT) for intermediate-stage disease. Systemic treatment, which uses mainly targeted drugs, is the standard therapy against advanced HCC. Sorafenib is an important first-line therapy for advanced HCC. As a classically effective drug, sorafenib can increase overall survival markedly. However, it still has room for improvement because of the heterogeneity of HCC and acquired resistance. Scientists have reported the acquired sorafenib resistance is associated with the anomalous expression of certain genes, most of which are also related with HCC onset and development. Combining sorafenib with inhibitors targeting these genes may be an effective treatment. Combined treatment may not only overcome drug resistance, but also inhibit the expression of carcinoma-related genes. This review focuses on the current status of sorafenib in advanced HCC, summarizes the inhibitors that can combine with sorafenib in the treatment against HCC, and provides the rationale for clinical trials of sorafenib in combination with other inhibitors in HCC. The era of sorafenib in the treatment of HCC is far from over, as long as we find better methods of medication.

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“…Its complex pathogenesis and molecular heterogeneity hinder HCC early diagnosis, making curative treatments impossible [15]. In these cases, systemic therapy is used, utilizing two available tyrosine kinase inhibitors (TKIs), sorafenib and lenvatinib, in the first-line setting for advanced HCC [16]. Regardless of its effectiveness, liver cancer cells are able to develop sorafenib resistance after sustained administration [17], where several TKIs (regorafenib and cabozantinib) and monoclonal antibodies (nivolumab, pembrolizumab and ramucirumab) have been recently approved [16].…”

Section: Introductionmentioning

confidence: 99%

“…In these cases, systemic therapy is used, utilizing two available tyrosine kinase inhibitors (TKIs), sorafenib and lenvatinib, in the first-line setting for advanced HCC [16]. Regardless of its effectiveness, liver cancer cells are able to develop sorafenib resistance after sustained administration [17], where several TKIs (regorafenib and cabozantinib) and monoclonal antibodies (nivolumab, pembrolizumab and ramucirumab) have been recently approved [16]. Considering toxicity and adverse reactions caused by these chemotherapeutic agents, some investigations have focused on the study of antitumor effects of natural compounds against HCC, such as resveratrol, curcumin and melatonin [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Antitumor Effects of Quercetin in Hepatocarcinoma In Vitro and In Vivo Models: A Systematic Review

et al. 2019

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Quercetin is a flavonoid present in fruits, vegetables and plants with antioxidant, anti-inflammatory and anticancer properties. Its beneficial activities have been demonstrated in different human pathologies, including hepatoprotective effects against liver disorders. High mortality and late diagnosis of the primary liver tumor hepatocarcinoma (HCC) makes this cancer an interesting target for the study of quercetin effects. Our aim was to systematically review antitumor activities of quercetin in HCC preclinical studies employing single, encapsulated, combined or derived quercetin forms. Literature search was conducted in PubMed, Scopus and Web of Science (WOS), and 39 studies were finally included. We found that 17 articles evaluated quercetin effects alone, six used encapsulated strategy, 10 combined this flavonoid, two decided to co-encapsulate it and only four studied effects of quercetin derivatives, highlighting that only nine included in vivo models. Results evidence the quercetin antiproliferative and proapoptotic properties against HCC either alone and with the mentioned strategies; nevertheless, few investigations assessed specific activities on different processes related with cancer progression. Overall, further studies including animal models are needed to deeper investigate the precise mechanisms of action of quercetin as antitumor agent, as well as the potential of novel strategies aimed to improve quercetin effects in HCC.

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Anti-tumoral activity of single and combined regorafenib treatments in preclinical models of liver and gastrointestinal cancers

Cited by 60 publications

References 88 publications

Melatonin as an Antitumor Agent against Liver Cancer: An Updated Systematic Review

Melatonin as an Antitumor Agent against Liver Cancer: An Updated Systematic Review

Is the era of sorafenib over? A review of the literature

Antitumor Effects of Quercetin in Hepatocarcinoma In Vitro and In Vivo Models: A Systematic Review

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