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Currently, chemotherapy is the main treatment for tumors, but there are still problems such as unsatisfactory chemotherapy results, susceptibility to drug resistance, and serious adverse effects. Natural compounds have numerous pharmacological activities which are important sources of drug discovery for tumor treatment. The combination of chemotherapeutic drugs and natural compounds is gradually becoming an important strategy and development direction for tumor treatment. In this paper, we described the role of natural compounds in combination with chemotherapeutic drugs in synergizing, reducing drug resistance, mitigating adverse effects and related mechanisms, and providing new insights for future oncology research. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC), the most prevalent subtype of liver cancer, is the second main reason for cancer-related deaths worldwide. In recent decades, sufficient evidence supported that immunotherapy was a safe and effective treatment option for HCC. However, tolerance and frequent recurrence and metastasis occurred in patients after immunotherapy due to the complicated crosstalk in the tumor immunosuppressive microenvironment (TIME) in HCC. Therefore, elucidating the TIME in HCC and finding novel modulators to target TIME for attenuating immune suppression is critical to optimize immunotherapy. Recently, studies have shown the potentially immunoregulatory activities of natural compounds, characterized by multiple targets and pathways and low toxicity. In this review, we concluded the unique role of TIME in HCC. Moreover, we summarized evidence that supports the hypothesis of natural compounds to target TIME to improve immunotherapy. Furthermore, we discussed the comprehensive mechanisms of these natural compounds in the immunotherapy of HCC. Accordingly, we present a well-grounded review of the naturally occurring compounds in cancer immunotherapy, expecting to shed new light on discovering novel anti-HCC immunomodulatory drugs from natural sources. [ABSTRACT FROM AUTHOR]

Simple Summary: The application of IL-2 for treating cancer is limited owing to its toxicity and short half-life. Its high binding ability to IL-2 receptor α expands immunosuppressive Treg cells, which represents an undesirable toxicity in cancer immunotherapy. Moreover, its small molecular size is the reason for its short half-life. We solved these problems by using a covalent modification strategy of IL-2 variant IL-2K35C with fatty acid by maleimide chemistry, namely, IL-2K35C-moFA. The experiments performed in vitro and in vivo proved that IL-2K35C-moFA is a novel immunotherapeutic agent with the potential to selectively stimulate CD8+ T cells and NK cells. Compared to IL-2WT, IL-2K35C-moFA showed a specifically reduced potency for the stimulation of Treg cells. Our results also showed that fatty acid conjugation appears to be effective in half-life extension. The combination of selective lymphocyte expansion and its long half-life means IL-2K35C-moFA should be evaluated as a potential human immunotherapeutic in the future. Human interleukin 2 (IL-2) has shown impressive results as a therapeutic agent for cancer. However, IL-2-based cancer therapy is limited by strong Treg amplification owing to its high binding affinity to IL-2 receptor α (IL-2Rα) and its short half-life owing to its small molecular size. In this study, we solved these problems using a covalent modification strategy of the IL-2 variant, i.e., substituting cysteine (C) for lysine (K) at position 35, using octadecanedicarboxylic acid through maleimide chemistry, creating IL-2K35C-moFA. IL-2K35C-moFA was equipotent to human IL-2 wild type (IL-2WT) in activating tumor-killing CD8+ memory effector T cells (CD8+ T) and NK cells bearing the intermediate affinity IL-2 receptors, and less potent than IL-2WT on CTLL-2 cells bearing the high-affinity IL-2 receptors. Moreover, it was shown to support the preferential activation of IL-2 receptor β (IL-2Rβ) over IL-2Rα because of the mutation and fatty acid conjugation. In a B16F10 murine tumor model, IL-2K35C-moFA showed efficacy as a single dose and provided durable immunity for 1 week. Our results support the further evaluation of IL-2K35C-moFA as a novel cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Dalbavancin is a novel semisynthetic glycopeptide antibiotic that comprises multiple homologs and isomers of similar polarities. However, pharmacokinetic studies have only analyzed the primary components of dalbavancin, namely B0 and B1. In this study, an ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed to simultaneously determinate and investigate the five homologous components of dalbavancin, namely, A0, A1, B0, B1, and B2, in rat plasma. In this method, methanol was used to precipitate plasma, and a triple-bonded alkyl chromatographic column was used for molecule separation, using 0.1% formic acid-acetonitrile as the mobile phase for gradient elution. Targeted homologs were analyzed by a triple quadrupole mass spectrometer using positive electrospray ionization in multiple reaction monitoring mode. The linearity range was 50–2500 ng/mL with a high correlation coefficient (r2 > 0.998). This method was successfully applied in the pharmacokinetic analysis of dalbavancin hydrochloride to investigate dalbavancin components in rats. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC), the most prevalent subtype of liver cancer, is the second main reason for cancer-related deaths worldwide. In recent decades, sufficient evidence supported that immunotherapy was a safe and effective treatment option for HCC. However, tolerance and frequent recurrence and metastasis occurred in patients after immunotherapy due to the complicated crosstalk in the tumor immunosuppressive microenvironment (TIME) in HCC. Therefore, elucidating the TIME in HCC and finding novel modulators to target TIME for attenuating immune suppression is critical to optimize immunotherapy. Recently, studies have shown the potentially immunoregulatory activities of natural compounds, characterized by multiple targets and pathways and low toxicity. In this review, we concluded the unique role of TIME in HCC. Moreover, we summarized evidence that supports the hypothesis of natural compounds to target TIME to improve immunotherapy. Furthermore, we discussed the comprehensive mechanisms of these natural compounds in the immunotherapy of HCC. Accordingly, we present a well-grounded review of the naturally occurring compounds in cancer immunotherapy, expecting to shed new light on discovering novel anti-HCC immunomodulatory drugs from natural sources.

A series of novel indene-derived retinoic acid receptor α (RARα) agonists have been designed and synthesized. The use of receptor binding, cell proliferation and cell differentiation assays demonstrated that most of these compounds exhibited moderate RARα binding activity and potent antiproliferative activity. In particular, 4-((3-isopropoxy-2,3-dihydro-1 H -inden-5-yl)-carbamoyl)benzoic acid ( 36d ), which showed a moderate binding affinity, exhibited a great potential to induce the differentiation of NB4 cells (68.88% at 5 μM). Importantly, our work established indene as a promising skeleton for the development of novel RARα agonists.