An Insight Into the Role of Alpha-Fetoprotein (AFP) in the Development and Progression of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the primary malignancy of hepatocytes and the second most common cause of cancer-related mortality across the globe. Despite significant advancements in screening, diagnosis, and treatment modalities for HCC, the mortality-to-incidence ratio remain unacceptably high. A recent study indicates that a minor population of HCCs are AFP negative or express the normal range of AFP levels. Although it is a gold standard and a more reliable biomarker in the advanced stage of HCC and poorly differentiated tumors, it does not serve as a suitable means for screening HCC. AFP plays a significant role in the development and progression of HCC and understanding its role is crucial. By examining the molecular mechanisms involved in AFP-mediated tumorigenesis, we can better understand HCC pathogenesis and identify potential therapeutic targets. This article details the role of alpha-fetoprotein (AFP) in the carcinogenic transformation of hepatocytes. The article also focuses on information about the structure, biosynthesis, and regulation of AFP at the gene level. Additionally, it discusses the immune evasion, metastasis, and control of gene expression that AFP mediates during HCC.

Decoding the Mechanism of Drugs of Heterocyclic Nature against Hepatocellular Carcinoma.

OBJECTIVES: Hepatocellular carcinoma (HCC) is the sixth most common type of cancer and accounts for ~90% of cases, with an approximated incidence of >1 million cases by 2025. Currently, the backbone of HCC therapy is the oral multi-kinase inhibitor, Sorafenib, which consists of a Pyridine heterocycle ring system. This review highlights the introspective characteristics of seven anticancer drugs of heterocyclic nature against HCC along with their structural activity relationships and molecular targets. METHODS: Literature collection was performed using PubMed, Google Scholar, SCOPUS, and Cross ref. Additional information was taken from the official website of the FDA and GLOBOCAN. Key findings/ Results: Based on the available literature, approved heterocyclic compounds show promising results against HCC, including Sorafenib (Pyridine), Regorafenib (Pyridine), Lenvatinib (Quinoline), Cabozantinib (Quinoline), Gemcitabine (Pyrimidine), 5-Fluorouracil (Pyrimidine)and Capecitabine (Pyrimidine), their mechanism of action and key aspects regarding its structural activity were included in the review. CONCLUSION: Heterocyclic compounds represent almost two-thirds of the novel drugs approved by FDA between 2010 and 2020 against Cancer. This review summarizes the clinical relevance, mechanism of action, structural activity relationship, and challenges of the seven available anticancer drugs with heterocyclic ring systems against HCC.

Green Synthesized Nanoparticles as a Plausible Therapeutic Strategy Against Hepatocellular Carcinoma: An Update on its Preclinical and Clinical Relevance.

Green nanotechnology can offer notable advantages over the conventional drug delivery methods in terms of improved drug stability, drug-carrying capacity, site-specificity, and feasibility to apply different routes of administration with less systemic toxicities. Metal nanoparticles bio fabricated with phytoconstituents and microbial extracts have gained significant interest for the treatment of various solid tumors including hepatocellular carcinoma. Hepatocellular carcinoma (HCC) is an aggressive cancer with a very poor prognosis. The current treatments of HCC fails to provide tumor specificity, causing many systemic toxicities and poor overall survival benefits especially for patients in advanced and terminal stages. A novel therapeutic approach with maximal therapeutic effect and minimum adverse effects are urgently required for HCC patients. Green synthesized metal nanoparticles offer significant anticancer effects along with minimal systemic toxicities because of their site-specific delivery into the tumor microenvironment (TME). Green synthesized metal nanoparticles can therefore be a highly beneficial strategy for the treatment of HCC if properly validated with preclinical and clinical studies. This review focuses on the preclinical evidence of the most widely studied green metal nanoparticles such as green synthesized silver nanoparticles, gold nanoparticles and selenium nanoparticles. We have also summarised the clinical studies and the patents approved for nanoparticles against HCC.

Biology, Significance and Immune Signaling of Mucin 1 in Hepatocellular Carcinoma.

Mucin 1 (MUC 1) is a highly glycosylated tumor-associated antigen (TAA) overexpressed in hepatocellular carcinoma (HCC). This protein plays a critical role in various immune-mediated signaling pathways at its transcriptional and post-transcriptional levels, leading to immune evasion and metastasis in HCC. HCC cells maintain an immune-suppressive environment with the help of immunesuppressive tumor-associated antigens, resulting in a metastatic spread of the disease. The development of intense immunotherapeutic strategies to target tumor-associated antigen is critical to overcoming the progression of HCC. MUC 1 remains the most recognized tumor-associated antigen since its discovery over 30 years ago. A few promising immunotherapies targeting MUC 1 are currently under clinical trials, including CAR-T and CAR-pNK-mediated therapies. This review highlights the biosynthesis, significance, and clinical implication of MUC 1 as an immune target in HCC.

Harnessing the immune system against cancer: current immunotherapy approaches and therapeutic targets.

Cancer immunotherapy is a rapidly evolving concept that has been given the tag "fifth pillar" of cancer therapy while radiation therapy, chemotherapy, surgery and targeted therapy remain the other four pillars. This involves the stimulation of the immune system to control tumor growth and it specifically targets the neoplastic cells rather than the normal cells. Conventional chemotherapy has many limitations which include drug resistance, recurrence of cancer and severe adverse effects. Immunology has made major treatment breakthroughs for several cancers such as colorectal cancer, prostate cancer, breast cancer, lung cancer, liver cancer, kidney cancer, stomach cancer, acute lymphoblastic leukaemia etc. Currently, therapeutic strategies harnessing the immune system involve Checkpoint inhibitors, Chimeric antigen receptor T cells (CAR T cells), Monoclonal antibodies, Cancer vaccines, Cytokines, Radio-immunotherapy and Oncolytic virus therapy. The molecular characterization of several tumor antigens (TA) indicates that these TA can be utilized as promising candidates in cancer immunotherapy strategies. Here in this review, we highlight and summarize the different categories of emerging cancer immunotherapies along with the immunologically recognized tumor antigens involved in the tumor microenvironment.

Insights into an Immunotherapeutic Approach to Combat Multidrug Resistance in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) has emerged as one of the most lethal cancers worldwide because of its high refractoriness and multi-drug resistance to existing chemotherapies, which leads to poor patient survival. Novel pharmacological strategies to tackle HCC are based on oral multi-kinase inhibitors like sorafenib; however, the clinical use of the drug is restricted due to the limited survival rate and significant side effects, suggesting the existence of a primary or/and acquired drug-resistance mechanism. Because of this hurdle, HCC patients are forced through incomplete therapy. Although multiple approaches have been employed in parallel to overcome multidrug resistance (MDR), the results are varying with insignificant outcomes. In the past decade, cancer immunotherapy has emerged as a breakthrough approach and has played a critical role in HCC treatment. The liver is the main immune organ of the lymphatic system. Researchers utilize immunotherapy because immune evasion is considered a major reason for rapid HCC progression. Moreover, the immune response can be augmented and sustained, thus preventing cancer relapse over the post-treatment period. In this review, we provide detailed insights into the immunotherapeutic approaches to combat MDR by focusing on HCC, together with challenges in clinical translation.

Cogent role of flavonoids as key orchestrators of chemoprevention of hepatocellular carcinoma: A review.

Chemopreventive approaches with food-derived phytochemicals are progressively rising as a significant aspect of tumor management and control. Herein, we have showcased the major phytoconstituents belonging to the group of flavanoid, as anti-cancer agents used for the treatment and prevention of hepatocellular carcinoma (HCC). Sorafenib is the sole drug used for the treatment of advanced HCC, but its clinical application is limited because of its severe adverse effects and drug resistance. Diet-based chemoprevention seems to be the way forward for this disease of malignant nature. As HCC is derived from a chronic inflammatory milieu, the regular incorporation of bioactive phytochemicals in the diet will confer protection and prevent progression to hepatocarcinogenesis. Many preclinical studies proved that the health benefits of flavonoids confer cytotoxic potential against various types of cancers including hepatocellular carcinoma. As flavonoids with excellent safety profile are abundantly present in common vegetables and fruits, they can be better utilized for chemoprevention and chemosensitization in such chronic condition. This review highlights the plausible role of the eight most promising flavonoids (Curcumin, Kaempferol, Resveratrol, Quercetin, Silibinin, Baicalein, Galangin and Luteolin) as key orchestrators of chemoprevention in hepatocellular carcinoma with preclinical and clinical evidence. An attempt to address the challenges in its clinical translation is also included. This review also provides an insight into the close association of HCC and metabolic disorders which may further decipher the chemopreventive effect of dietary bioactive from a proof of concept to extensive clinical translation. PRACTICAL APPLICATIONS: According to GLOBOCAN 2020 database, it is estimated that 905,677 new cases of liver cancer and approximately 830,180 deaths related to that. The cancer incidence and mortality are almost similar as it is diagnosed at an advanced stage in patients where systemic drug therapy is the sole approach. Due to the emergence of multidrug resistance and drug-related toxicities, most of the patient can not adhere to the therapy regimen. Flavonoids are known to be a potential anticancer agent with an excellent safety profile. These are found to be effective preclinically against hepatocellular carcinoma through modulation of numerous pathways in hepatocarcinogenesis. But, the bioavailability issue, lack of well designed-validated clinical evidence, the possibility of food-drug interaction etc limit its clinical utility. The research inputs mainly to overcome pharmacokinetic issues along with suitable validation of efficacy and toxicity will be a critical point for establishing flavonoids as an effective, safe, affordable therapeutics.

Anti-VEGF Mediated Immunomodulatory Role of Phytochemicals: Scientific Exposition for Plausible HCC Treatment.

Hepatocellular carcinoma (HCC) is one of the most common solid tumours and the second leading cause of cancer-related mortality worldwide. Advanced-recurrent HCC often requires a systemic drug therapy where multi tyrosine kinase inhibitor, Sorafenib represents the first-line therapy option. But it exhibited very limited survival benefit and tumour response due to the early emergence of drug resistance and drug-related adverse effect. Immunotherapy approaches now being widely studied as an effective alternative treatment for HCC. Several immune checkpoint inhibitors (ICI), such as Nivolumab and Pembrolizumab, are approved as monotherapy in sorafenib-resistant HCC patients. But, the existence of a plethora of immunosuppressive signals in the tumour microenvironment often leads to unsuccessful immunotherapies. In this context, combinatorial immunotherapies are getting much acceptance as a way to improve therapeutic outcomes by blocking immunosuppressive signals in the tumour microenvironment (TME). The combination of Vascular Endothelial Growth Factor (VEGF) inhibitors with ICI resulted in significant synergistic effects in various preclinical and clinical studies. However, the adverse effects associated with current synthetic VEGF inhibitors limit its clinical utility. In this review, we have summarized the potential of phytochemicals, especially the category of flavonoids, alkaloids, glycosides, terpenoids, and coumarin, as the available-affordable-safe-effective repositories of VEGF inhibitors. Their possibilities as an alternative for synthetic VEGF inhibitors by synergistic combination with ICI are reviewed, thereby enhancing patient compliance and survival rates. This review highlights the demand for a detailed investigation of the plausible role of plant-based anti-angiogenic-immunotherapy combination against HCC.