Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 23, Issue 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.

By triggering immune responses in malignancies that have generally been linked to poor outcomes, immunotherapy has recently shown effectiveness. On the other hand, tumors provide an environment for cells that influence the body’s immunity against cancer. Malignant cells also express large amounts of soluble or membrane-bound ligands and immunosuppressive receptors. In this regard, the combination of oncolytic viruses with pro-inflammatory or inflammatory cytokines, including IL-2, can be a potential therapy for some malignancies. Indeed, oncolytic viruses cause the death of cancerous cells and destroy the tumor microenvironment. They result in the local release of threat signals and antigens associated with tumors. As a result, it causes lymphocyte activity and the accumulation of antigenpresenting cells which causes them to accumulate in the tumor environment and release cytokines and chemokines. In this study, we reviewed the functions of IL-2 as a crucial type of inflammatory cytokine in triggering immune responses, as well as the effect of its release and increased expression following combination therapy with oncolytic viruses in the process of malignant progression, as an essential therapeutic approach that should be taken into consideration going forward.

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.

Objectives: This study aimed to investigate the performance of Pulsatilla saponin A (PsA) in diffuse large B-cell lymphoma (DLBCL) cells. Methods: Proliferation, ELISA, apoptosis, cell cycle analysis, and assays were carried out to detect the growth and apoptosis in DLBCL cells. Western blotting was used to identify the change in the protein. Results: In cell assays, PsA significantly inhibited the growth and apoptosis in DLBCL cells. The IL-10 and TNF-α of OCI-LY10 and U2932 cells were reduced after 24 h PsA treatment. Bax, cleaved PARP, and cleaved Caspase-3 were increased, while Bcl-2 and C-Myc decreased after PsA treatment. IL-10 may regulate the expression of C-Myc protein in cells by activating the JAK2/STAT3 signaling pathway. PsA can inhibit the overexpression of p-JAK2 and p- STAT3 signaling pathways induced by IL-10 stimulants. The proliferation and apoptosis induced by PsA were confirmed in DLBCL cells. Conclusion: Our findings revealed that PsA may exert its antitumor effect by causing G1 arrest and apoptosis in DLBCL cells. The mechanism of PsA regulating apoptosis in DLBCL cells is probably through the JAK2/STAT3 signaling pathway in vitro.

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.

Background: Targeted therapies, specifically ErbB family tyrosine kinase inhibitors, have demonstrated potential for improving outcomes in patients with ErbB2-positive breast cancer. Despite their effectiveness, these therapies are associated with limitations, including high costs, side effects, drug resistance, lack of specificity, and toxicity. To overcome these challenges, drug repurposing has emerged as a promising strategy in breast cancer treatment. Objective: The aim of this investigation was to assess the influence of calcitriol on breast cancer cell lines expressing ErbB2 and comparing its effects with the conventional treatment, neratinib. Methods: We employed an MTT test to determine cell viability and utilized staining techniques to assess cell apoptosis. Flow cytometry was used to evaluate cell cycle arrest, while a scratch wound healing test was performed to examine cancer cell migration ability. Additionally, gene expression studies were conducted for calcitriol and neratinib to support our hypothesis regarding the ErbB2 gene. Results: The repurposing of calcitriol demonstrated enhanced efficacy in suppressing cancer cell growth in ErbB2- positive breast cancer. Proportionally, calcitriol significantly reduced the viability of SK-BR-3 cells, similar to neratinib. Furthermore, calcitriol exhibited significant cytotoxicity against neratinib and substantially reduced breast cancer cell growth. These findings were corroborated by the wound healing assay, cell cycle arrest analysis, and gene expression studies, demonstrating comparable efficacy to the standard treatment, neratinib. Conclusion: The findings from this investigation offer compelling proof that highlights the promising role of calcitriol as an adjuvant drug with antiproliferative and antitumoral effects in the management of ErbB2-positive breast carcinoma patients. Therefore, we recommend further evaluation of calcitriol in clinical settings, particularly for the treatment of ErbB2-positive breast cancer, as it shows promise as a valuable therapeutic option.