卷 23, 编号 18 (2023)

Nanoformulations derived from natural products are gaining popularity as a treatment option for several human diseases, including cancer, as they offer a viable alternative to conventional cancer therapies, which are often associated with numerous side effects and complications. Quercetin (Que), a plant-derived phenolic molecule, has demonstrated potential as a chemotherapeutic agent for different types of cancer. However, Que's low water solubility, instability towards antioxidants, low bioavailability, and severe biotransformation constraints make it challenging to use in vivo. Nanoparticles have emerged as a promising technology for the precise targeting of tumor cells, leading to improved efficacy and specificity in cancer therapies. In this review, the impact of flavonoid nanoformulations on enhancing the safety, therapeutic potential, and bioavailability of Que in cancer treatment is highlighted. A variety of nanoparticle types have been developed, including polymeric micelles, liposomes, PLGA nanoparticles, coencapsulation, chitosan NPs, lipid carriers, silver and gold NPs, inorganic NPs, organic metal frameworks, and biomacromolecule- based NPs, all aimed at improving the antineoplastic efficacy of Que. These nanoparticles offer several advantages, including prolonged circulation time, tumor-specific biodistribution, high encapsulation efficiency, enhanced therapeutic efficacy, and controlled release. This review provides fresh insights into the arena of drug discovery for tumor therapies by focusing on the influence of flavonoid nanoformulations on the enhancement of their safety, therapeutic, and bioavailability characteristics.

Aims:More effective treatment options for patients with renal cell carcinoma (RCC) are needed, in particular advanced RCC.

Background: Sunitinib, a multitarget tyrosine kinase inhibitor, is a first-line treatment of metastatic RCC. However, the management of sunitinib-induced adverse events and resistance is complex. In hematological malignancies, effective targeting of anti-apoptotic proteins such as Bcl-2 has been achieved, but limited progress has been made in solid tumors.

Objective: This work systematically investigated the therapeutic potential of the combination of sunitinib and venetoclax, a Bcl-2 inhibitor, in preclinical RCC models.

Methods: Quantitative analysis of drug interactions was performed. Cell viability was examined after drug treatment or Bcl-2 siRNA depletion. RCC xenograft mouse model was applied to validate the efficacy of sunitinib and venetoclax.

Results: A strong synergistic interaction between sunitinib and venetoclax was observed across a range of different dose levels in all tested RCC cell lines. Sequential treatment studies show that the sequential addition of venetoclax and then sunitinib is superior to concurrent treatment and the sequential addition of sunitinib and then venetoclax in decreasing RCC cell viability. The sensitivity of RCC cell lines to venetoclax treatment negatively correlates with their Bcl-2 levels. Specific depletion of Bcl-2 mimics the synergistic effects of venetoclax with sunitinib. Treatment of mice implanted with high Bcl-2-expressing RCC cells reveals that a combination of venetoclax and sunitinib at a non-toxic dose displays complete regression of tumor growth throughout the whole duration of treatment.

Conclusion: Our work demonstrates that inhibiting Bcl-2 by venetoclax synergistically enhances sunitinib's efficacy in RCC. Venetoclax holds great potential as a viable option for clinical use.

Background: In cancer, Receptor tyrosine kinases (RTKs) are powerful oncoproteins that can lead to uncontrolled cell proliferation, angiogenesis, and metastasis when mutated or overexpressed, making them crucial targets for cancer treatment. In endothelial cells, one of them is vascular endothelial growth factor receptor 2 (VEGFR2), a tyrosine kinase receptor that is produced and is the most essential regulator of angiogenic factors involved in tumor angiogenesis. So, a series of new N-(4-(4-amino-6,7-dimethoxyquinazolin-2-yloxy)phenyl)-N-phenyl cyclopropane-1,1- dicarboxamide derivatives as VEGFR-2 inhibitors have been designed and synthesized.

Methods: The designed derivatives were synthesized and evaluated using H-NMR, C13-NMR, and Mass spectroscopy. The cytotoxicity was done with HT-29 and COLO-205 cell lines. The potent compound was further studied for Vegfr- 2 kinase inhibition assay. Furthermore, the highest activity compound was tested for cell cycle arrest and apoptosis. The molecular docking investigation was also done with the help of the Glide-7.6 program interfaced with Maestro- 11.3 of Schrodinger 2017. The molecular dynamics simulation was performed on the Desmond module of Schrodinger.

Results: Compound SQ2 was observed to have promising cytotoxic activity (IC50 = 3.38 and 10.55 µM) in comparison to the reference drug Cabozantinib (IC50 = 9.10 and 10.66 µM) against HT-29 and COLO-205, respectively. The synthesized compound SQ2 showed VEGFR-2 kinase inhibition activity (IC50 = 0.014 µM) compared to the reference drug, Cabozantinib (IC50 = 0.0045 µM). Moreover, compound SQ2 strongly induced apoptosis by arresting the cell cycle in the G1 and G2/M phases. The docking study was performed to understand the binding pattern of the new compounds to the VEGFR-2 active site. Docking results attributed the potent VEGFR-2 inhibitory effect of the new compounds as they bound to the key amino acids in the active site, Asp1044, and Glu883, as well as their hydrophobic interaction with the receptor's hydrophobic pocket. The advanced computational study was also done with the help of molecular dynamics simulation.

Conclusion: The findings show that the developed derivatives SQ2 and SQ4 are equally powerful as cabozantinib at cellular and enzymatic levels. The apoptosis and cell cycle results show that the proposed compounds are potent. This research has provided us with identical or more potent VEGFR-2 inhibitors supported by the results of docking studies, molecular dynamics simulation, cytotoxic actions, in vitro VEGFR-2 inhibition, apoptosis, and cell cycle arrest.