Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 25, Issue 15, 2025

Hepatocellular Carcinoma (HCC) is a primary hepatic tumor and is one of the world's third most frequent malignancies after lung and colorectal. After stomach, lung, and colorectal cancers, it is the most common cause of cancer-related mortality. Since the Palaeolithic era, herbs have been used as an essential source of alternative drugs. Modern cancer treatments that use chemotherapeutic medications are made of chemicals derived from plants.

The present review is about the compilation of phytochemical extracts and molecules from 2020 to July 2024.

A detailed literature survey was conducted to compile data from PubMed, Sci Finder, Science Direct, Google, etc.

The identification of novel treatments and their combinations for usage in the adjuvant context potentially address significant unmet needs in the management of HCC. A large number of investigations have been carried out these days on plants. Numerous phytochemicals included in plant extract may possess anti-cancer properties, including the ability to induce cell cycle arrest, suppress cell proliferation, increase apoptosis, and obstruct migration, invasion, and metastasis. These approaches possess less hazardous and more effective treatment in HCC.

This article is the compilation of data about research on phytomolecules and herbal extracts from January 2020 to July 2024 for the treatment of HCC in vitro and in-vivo. Various mechanisms involved in the treatment are also explored in the article. The growing interest of researchers in investigating new approaches toward HCC management with phytomolecules is rapidly growing.

Breast cancer is the most common cancer in women. Traditional treatments include endocrine therapy, chemotherapy, surgery, radiation, and immunotherapy. Recent studies suggest melittin, a component of bee venom, as a promising breast cancer treatment due to its anticancer properties: inducing cytotoxicity, apoptosis, and gene regulation.

This manuscript aims to review melittin's potential therapeutical and future implications in treating breast cancer. An extensive literature search was conducted on MEDLINE and Cochrane databases up to July 2024 using Boolean operators with a combination of keywords. After screening, data extraction, and descriptive analysis, 40 articles were retained.

Experimental data and different therapeutical strategies were collected. Melittin disrupts tumor cell membranes and modulates key apoptotic pathways. Advanced delivery systems enhance their effectiveness and reduce toxicity. Combining melittin with chemotherapy shows synergistic effects, improving outcomes. Thus, melittin could be a valuable addition to breast cancer therapies.

Further clinical trials are essential to validate its potential and establish its role in breast cancer therapy.

This study explored whether the cell cycle regulator cadherin 1 (CDH1) impacts colorectal cancer cell cycle and stemness via mediating ubiquitination of sirtuin 5 (SIRT5).

We first constructed CDH1 overexpression plasmid and small interfering RNA against SIRT5 (siSIRT5) and transfected them into HCT116/HT29 cells, followed by transfection efficiency verification. The effect of CDH1 on Cyclin F/SIRT5/CDH1 protein levels in HCT116/HT29 cells was verified by Western blot. After up-regulation of CDH1, changes in SIRT5 ubiquitination (immunoprecipitation), cell cycle (cell cycle kit), proliferation (5-Bromodeoxyuridine assay), and stemness marker expressions (qRT-PCR) in HCT116/HT29 cells were detected. Rescue assays were performed to examine cell proliferation and stemness marker expressions.

Overexpression of CDH1 decreased Cyclin F expression and increased SIRT5 and CDH1 expressions in HCT116/HT29 cells. Up-regulation of CDH1 suppressed SIRT5 ubiquitination, promoted G0/G1 phase blockage in HCT116/HT29 cells, boosted cell proliferation into quiescence and enhanced cell stemness. siSIRT5 counteracted the regulatory effect of CDH1 overexpression on colorectal cancer cells.

CDH1 promotes the entry of colorectal cancer cells into quiescence and enhances stemness by dampening SIRT5 ubiquitination.

Cancer chemotherapy is one of the best ways to treat the patients with cancer as they can remove cancer cells, which can not be remove by radiation or surgery.

Our study is focused on identifying potent chemotherapeutic drugs with minor or no adverse side effects. Therefore, in this study, we aimed to synthesize ethyl 4-[(4-methylbenzyl)oxy] benzoate complex, a macrocyclic aromatic compound followed by testing its antineoplastic activity against Ehrlich ascites carcinoma (EAC) and human breast cancer (MCF7) cells.

In vitro and in vivo assays were used for monitoring, cytotoxicity, tumor weight, survival time, tumor cell growth inhibition, and hematological parameters to investigate the anticancer effectiveness of the tested compound. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was used to examine the expression of growth and apoptotic related genes. Haematological and biochemical parameters were assessed to examine the host toxicity in mice.

The compound exhibited notable anticancer activity against both EAC and MCF7 cells. It showed 40.70 and 58.98% cell growth inhibition at the doses of 0.5 and 1.00 mg/kg, respectively in comparison to that of control EAC-bearing mice (p < 0.0001). The result is comparable with clinically used chemotherapeutic drugs cisplatin (59.2% growth inhibition at the dose of 1.0 mg/kg body weight). A four folds reduction of tumor weight (volume) of treated group at higher dose (1.0 mg/kg/day) was noted in comparison to that of untreated EAC-bearing mice. Also, the mean survival time of treated mice (1.00 mg/kg) increased by more than 83.07% when compared to that of control EAC-bearing mice (p < 0.001). In addition, EAC-bearing control mice showed drastic deterioration of RBC, WBC, and % of hemoglobin, however, in the treated mice these parameters were restored towards normal levels. A dose dependent reduction of growth and proliferation of MCF7 cells was noted in compound treated cells. Most importantly, apoptosis of MCF7 was induced followed by activation of pro-apoptotic genes (p53, Bax, Parp, Caspase-3, -8, -9) and inactivation of antiapoptotic, e.g. Bcl2 gene. Toxicological studies reveal that there were minor changes in hematological (RBC, WBC, % of Hb) and biochemical (serum glucose, cholesterol, creatinine, SGOT, SGPT) parameters during the treatment period, however, the parameters returned towards normal levels after the treatment period, indicating no or minor toxic effect of the compound on the host.

The compound has promising anticancer activity with no or minimum host toxic effects. Thus, it has the potential to be formulated as an effective chemo-agent, however, further preclinical and clinical research is imperative using animal and human models.

Cervical cancer encompasses highly invasive and metastatic malignant tumors with poor prognoses. Recently, microneedles have gained significant attention as a novel, non-invasive drug delivery method, offering unique advantages in tumor treatment.

This study aims to develop an ulvan-based microneedle delivery system encapsulating the photosensitizer 5-aminolevulinic acid (5-ALA-UMNs) and to investigate its inhibitory effects on the growth of human cervical cancer Hela cells.

The 5-ALA-UMNs and UMNs (without photosensitizer) were fabricated using a two-step casting technique. The microneedles' morphology, puncture performance, and mechanical strength were assessed. Hela cells were treated in vitro with 5-ALA-UMNs, and the cellular uptake of the photosensitizer was observed using inverted fluorescence microscopy. Cell viability was determined by the CCK-8 assay to identify the optimal drug concentration. Additionally, the anti-tumor efficacy of 5-ALA-UMNs, induced via photodynamic therapy, was evaluated by Live-Dead staining and flow cytometry.

The microneedles exhibited a uniform quadrangular pyramidal shape, orderly arrangement, intact needle tips, and robust mechanical strength. Inverted fluorescence microscopy confirmed the successful uptake of the photosensitizer by Hela cells, which enzymatically converted it to the fluorescent compound protoporphyrin IX. CCK-8 assays demonstrated that 5-ALA-UMNs displayed favorable cytocompatibility and safety. Liver-dead staining revealed Hela cell survival rates as follows: 99.55% in the control group, 99.37% in the control microneedle group, 99.41% in the 5-ALA-UMNs group without light exposure, and 57.35% in the 5-ALA-UMNs group with light exposure (all p < 0.05). Flow cytometry results corroborated the live-dead staining findings, confirming the cytotoxic effect of 5-ALA-UMNs on tumor cells.

These results indicate that 5-ALA-UMNs hold promise as a tumor-targeting therapeutic.

According to the data, mutations in EGFR-related genes are the main cause of Non-Small Cell Lung Cancer (NSCLC), necessitating the development of new drug constructs for EGFR-TKIs particularly important. This study aimed to screen potential third-generation EGFR-TKIs to address the emerging drug resistance challenges in NSCLC.

In this study, virtual screening, molecular dynamics modeling, and bioactivity evaluation were carried out to find a potential EGFR inhibitor that could overcome the L858R/T790M mutation. At first, 12 potential compounds were screened step by step from about 250,000 structures by virtual screening. These 12 compounds were subjected to MTT antitumor activity evaluation and kinase inhibition assay to select compounds with strong antiproliferative effects on cancer cells. Then, the preferred compounds were subjected to time-dependent assay, scratch assay, AO staining assay, and hemolysis assay. Finally, the preferred compound was subjected to molecular docking and molecular dynamics simulation with 5HG7 protein.

The IC50 of T22306 on H1975 cells was 9.17 μM. In further kinase evaluation, the kinase inhibition of EGFR^L858R/T790M was 69.17%. In addition, time-dependent experiments and scratch and AO staining assays confirmed the potential of T22306 as an EGFR-TKI inhibitor, while hemolysis assays demonstrated no significant toxicity. Finally, molecular docking revealed the formation of critical hydrogen bonds between T22306 and LEU-718. Furthermore, molecular dynamics simulations showed that the T22306-5HG7 complex has a low binding energy (-117.73 ± 18.69 kJ/mol), thus suggesting that T22306 binds tightly to the target protein 5HG7.

In this study, we rapidly screened potential compounds against NSCLC with the help of virtual screening technology. Further in vitro experiments demonstrated that T22306 successfully overcame the L858R/T790M mutation and could be a potential epidermal growth factor receptor inhibitor.

Radioresistance is the primary cause of treatment failure in esophageal squamous cell carcinoma, emphasizing the importance of identifying effective radiosensitizers.

This study aimed to explore the effects and potential mechanisms of Eg5 inhibitor K858 on the radiosensitivity of esophageal squamous cell carcinoma TE-1 and KYSE150 cell lines, as well as xenografts (TE-1 cells).

Cellular function was assessed using CCK8, wound healing, and transwell invasion assays. Radiosensitivity parameters were derived from colony formation assays. Cell apoptosis and cell cycle were assessed using flow cytometry, whereas protein expression levels were detected using western blotting and immunohistochemistry. The xenograft model was used to observe the growth of tumors.

K858 inhibited the malignant functions of TE-1 and KYSE150 cell lines. Radiosensitivity parameters were reduced after K858 treatment. The combination of K858 and irradiation markedly suppressed cell proliferation, induced apoptosis, and stimulated cell cycle arrest during the irradiation-sensitive phase. Additionally, K858, combined with irradiation, significantly increased the expression of the epithelial-mesenchymal transition marker E-cadherin and decreased the expression of N-cadherin, vimentin, MMP2, and MMP9. K858, combined with irradiation, significantly inhibited tumor growth in xenograft models.

K858 enhanced the radiosensitivity of esophageal squamous cell carcinoma and affected the expression of epithelial-mesenchymal transition-related markers.