Mini Reviews in Medicinal Chemistry - Volume 23, Issue 11, 2023

Metformin is an oral hypoglycemic drug, the first option used to treat type 2 diabetes mellitus due to its high efficacy and low cost. Recently, it has drawn attention among researchers due to its new-found antitumor effect. Growing evidence showed that metformin could inhibit cancer progression, especially in hepatocellular carcinoma, and several clinical trials are underway. However, the underlying mechanisms of the inhibition of hepatocellular carcinoma remain to be further explored and clarified. Herein, we reviewed the latest findings of how metformin acts against hepatocellular carcinoma and the proposed mechanisms. In addition, we included related preclinical trials, along with the limitations and perspectives of its treatment in hepatocellular carcinoma, providing novel ideas for research to conquer hepatocellular carcinoma.

Gliomas are the most common malignant cancers of the brain that have unregulated proliferation and are known as highly invasive tumors. Hence, their relapse rate is high, and the prognosis is low. Despite remarkable advances in neuroimaging, neurosurgery, and radiation therapy, they, especially glioblastoma, are highly resistant to treatments, including radiotherapy, surgery, and temozolomide chemotherapy. The average survival rate for patients with malignant glioma is still less than two years. Accordingly, the search for new treatment options has recently become an urgent need. Today, a number of nutraceuticals have been considered because of their special role in inhibiting the angiogenic process, metastasis, and apoptosis, resulting in the inhibition of tumor growth, including glioma. Nutraceuticals can disrupt cancer cells by affecting different pathways. In fact, these compounds can reduce the growth of cancer cells, inhibit their proliferation and angiogenesis, as well as induce apoptosis in these cells and play an important role in various stages of treatment. One of the key targets of nutraceuticals may be to regulate cellular signaling pathways, such as PI3K/Akt/mTORC1, JAK/STAT, and GSK-3, or to exert their effects through other mechanisms, such as cytokine receptors and inflammatory pathways, reactive oxygen species, and miRNAs. This review refers to the results of recent studies and target molecules as well as signaling pathways affected by some nutraceuticals in glioma cells. These studies indicated that clinical trials are imminent and new approaches can be beneficial for patients.

Infections caused by the Hepatitis C virus (HCV) affect around 70 million people worldwide, leading to serious liver problems, such as fibrosis, steatosis, and cirrhosis, in addition to progressing to hepatocellular carcinoma and becoming globally the main cause of liver disease. Despite great therapeutic advances in obtaining pan-genotypic direct-acting antivirals (DAAs), around 5-10% of affected individuals are unable to eliminate the virus by their own immune system’s activity. Still, there are no licensed vaccines so far. In this context, the orchestrated process of virus entry into host cells is a crucial step in the life cycle and the infectivity capability of most viruses. In recent years, the entry of viruses has become one of the main druggable targets used for designing effective antiviral molecules. This goal has come to be widely studied to develop pharmacotherapeutic strategies against HCV, combined or not with DAAs in multitarget approaches. Among the inhibitors found in the literature, ITX 5061 corresponds to the most effective one, with EC⁵⁰ and CC⁵⁰ values of 0.25 nM and >10 μM (SI: 10,000), respectively. This SRBI antagonist completed the phase I trial, constituting a promising compound against HCV. Interestingly, chlorcyclizine (an antihistamine drug) showed action both in E1 apolipoproteins (EC⁵⁰ and CC⁵⁰ values of 0.0331 and 25.1 μM, respectively), as well as in NPC1L1 (IC⁵⁰ and CC⁵⁰ values of 2.3 nM and > 15 μM, respectively). Thus, this review will discuss promising inhibitors targeting HCV entry, discussing their SAR analyzes, recent contributions, and advances in this field.

Background: Trastuzumab is a monoclonal antibody that revolutionized the treatment of HER2+ breast cancer. However, about 30% of patients demonstrate resistance to this drug. Objective: The purpose of this study is to identify the mechanisms involved in resistance to treatment. with trastuzumab in women undergoing HER2+ breast cancer treatment. Methods: A wide review and meta-analysis were performed in the PubMed and Scielo databases up to January 2022. All articles that analyzed the efficacy of the drug in HER2+ human patients treated with trastuzumab were selected, except reviews, meta-analyses, and reports. Egger’s test was applied to verify publication bias. Forest plot and PRISMA flowchart were employed. Results: 60 articles were selected for the review and 15 included in the meta-analysis. A total of 102 resistance mechanisms were identified, 73 of which are different from each other. The mechanisms have been classified into 5 different categories. The main resistance mechanisms found are in the PI3K/Akt/mTOR pathway or related to low HER2, often resulting from failure to assess HER2 status. Both groups presented statistical significance. The two groups were not significantly different from each other. Conclusion: Drug resistance is the main challenge of trastuzumab-based treatment. To overcome this challenge, it is important to continue efforts to understand the mechanisms of cancer drug resistance, identify therapies that can treat refractory cancer to current therapies, and possibly create a panel of genes that predict resistance, avoiding symptomatic and economic costs. The main limitation of this study was the selection and population bias.