Anti-Cancer Agents in Medicinal Chemistry - Current Issue

In various kinds of cancer, including Non-Small Cell Lung Cancer (NSCLC), treatment resistance diminishes the effectiveness of current therapeutic approaches and underscores the need for new treatment strategies.

This study aimed to investigate the combined and individual effects of the anticancer drug carboplatin and the natural antioxidant curcumin, as well as the apoptotic effects of these drugs on the A549 cancer cells.

The synergistic effect of the combined treatment with curcumin and carboplatin on lung cancer cells was evaluated, focusing on early apoptosis, caspase-3/9 activity, and mitochondrial membrane potential.

The cytotoxic effects were determined using the MTT method. Apoptotic changes were examined using the Annexin V-FITC labeling method. Activation of caspases-9 and -3 and mitochondrial membrane potential were measured using flow cytometry.

The IC50 values of curcumin and carboplatin against A549 cells were determined to be 60±8 μM and 100±9 μM, respectively. The combination of curcumin and carboplatin showed a synergistic effect. After treating A549 cells with carboplatin, curcumin, or the combined use of curcumin+carboplatin for 12 hours, the rates of early apoptotic cells were determined to be 9.5±1.3%, 8.1±0.3%, and 22.2±2.9%, respectively. The rate of early apoptosis in combined use was significantly higher compared to individual use. Similarly, when the combined treatment of curcumin and carboplatin was compared to the administration of carboplatin alone, a higher level of mitochondrial membrane depolarization was observed. There was a slight increase in caspase 9 activity in the combined treatment group compared to the individual treatments. Furthermore, after treating A549 cells with the specified doses, the caspase 3 activity was determined for carboplatin (0.5±0.1%), curcumin (1.9±0.0%), and the combination of both (7.3±0.8%).

These results indicated that the combined use of curcumin and carboplatin enhanced apoptosis and mitochondrial depolarization, demonstrating that the combined treatment of drugs reduced the toxic dose of carboplatin. However, further research is needed to comprehensively understand the potential of this effect in in vivo studies.

Cancer is a global health burden. Despite advances in early detection and therapeutics, cancer prevalence continues to increase, underscoring the need for innovative therapeutic strategies. Dysregulation of cell death mechanisms is a hallmark of cancer that can lead to apoptosis evasion, which strongly contributes to tumor progression and therapy resistance. Isothiouronium salts have attracted attention as promising antitumor agents. This study aimed to evaluate the in vitro antitumor effect of an isothiouronium salt (IS-MF08) on the B16F10 melanoma cell line.

The antitumor properties of IS-MF08 were investigated by incubating B16F10 cells with the compound at different concentrations. Cytotoxicity was determined by the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay, cell cycle arrest and cell death mechanisms by flow cytometry, and morphological alterations by transmission electron microscopy. Physicochemical parameters related to drug-likeness were predicted in silico using the SwissADME tool.

IS-MF08 was cytotoxic to melanoma cells, triggering cell cycle arrest and disrupting mitosis. The mechanism of cell death was compatible with apoptosis, as indicated by annexin V-FITC experiments and the relevant morphological changes in cell structure observed by transmission electron microscopy. SwissADME predicted that IS-MF08 has good physicochemical properties related to absorption and permeation.

The numerous mechanisms of cell death triggered by IS-MF08 and its drug-likeness make it an interesting molecule in the search for new antitumor compounds, contributing to therapies targeting the dysregulation of cellular mechanisms such as apoptosis.

This study explores the therapeutic potential of Nigella sativa L. and its key bioactive compound, thymoquinone (TQ).

Pancreatic cancer presents a significant health challenge due to its aggressiveness and limited treatment options. N. sativa and its component TQ have demonstrated anticancer properties in other cancers, warranting exploration in pancreatic cancer models.

To assess the antiproliferative, apoptotic, and anti-invasive effects of N. sativa extracts and TQ on pancreatic cancer cells, with a focus on modulating the NRF2/HO-1 and TNF-α signaling pathways.

MIA PaCa-2 and PANC-1 pancreatic cancer cell lines were treated with essential and fixed oils, methanol extracts (from Türkiye and Syria), and TQ. Cell viability, apoptosis, and invasiveness were assessed via XTT, Annexin V, and Matrigel assays, respectively. Gene expression and cytokine levels were evaluated using RT-qPCR and ELISA. HPLC was conducted to confirm TQ concentrations in extracts.

The methanol extract of Türkiye-originated N. sativa seeds (TM) exhibited the highest cytotoxic effect, reducing cell viability in MIA PaCa-2 and PANC-1 at 0.05 mg/mL, while TQ significantly decreased viability at 20 µM. TM reduced MIA PaCa-2 and PANC-1 invasiveness (42 ± 1.23 and 35 ± 0.73, respectively) and contained a higher concentration of TQ (7.9168 ± 0.0561%) compared to the Syria-originated extract (SM).

The findings suggest that TM and TQ exhibit strong anticancer potential by modulating key signaling pathways in pancreatic cancer cells, supporting their potential for further development as therapeutic agents in pancreatic cancer treatment.

Monastrol is a known kinesin Eg5 inhibitor. It is a dihydropyrimidine with 4-(m-hydroxyphenyl) substituent. In contrast to taxols and vinca alkaloids, which, through targeting microtubules, affect both normal and cancer cells, kinesin inhibitors selectively target cancer cells.

In this study, m-hydroxyphenyl in monastrol was replaced with imidazolyl substituent, which has better water solubility and is found in the structure of many drugs and biologically active compounds. The effects of synthesized compounds were also investigated.

Three series of monastrol-related dihydropyrimidinone derivatives were synthesized through a modified Biginelli reaction. The newly synthesized compounds were characterized by elemental analysis, LCMS, and NMR. Then, the structure-activity relationship (SAR) of synthesized compounds was evaluated by their toxicity, molecular docking scores, and results of molecular dynamic simulation. The compounds with more potential (4i, 4m, 5a, and 6a) were further investigated in vitro and in vivo for their anti-cancer effects.

The synthesized compounds could effectively reduce the ATPase activity of kinesins, which was consistent with the observation of G2/M arrest of cells in flow cytometry and confocal microscopy results. In addition, an increase in cells in the sub-G1 phase, along with the enhancement of the Bax/Bcl-2 ratio and overexpression of caspases 3, 9, and 8, suggested the apoptosis-inducing effects of compounds. Moreover, compounds showed potent anti-angiogenic effects via altering the expression of genes involved in angiogenesis, which was consistent with the reduced length of capillaries in the CAM test. The synthesized compounds could also demonstrate satisfactory in vivo results in the mice tumor model, which was in accordance with the findings of in vitro experiments.

Novel dihydropyrimidinone derivatives synthesized via modified Biginelli reaction present promising potential as anti-cancer agents.

Lung cancer remains a leading cause of cancer-related mortality worldwide, primarily due to late-stage diagnosis and resistance to conventional therapies. Recent studies have highlighted the potential of natural compounds in enhancing the efficacy and reducing the side effects of conventional cancer treatments. Baicalin, a bioactive compound from Scutellaria baicalensis, exhibits significant anticancer properties.

This study aimed to investigate the role of baicalin in modulating lung cancer cell behavior through the arachidonate 12-lipoxygenase (ALOX12)-mediated ferroptosis pathway.

We employed cyber pharmacology and molecular docking techniques to predict and validate the interaction between baicalin and ALOX12. In vitro experiments were conducted on A549 lung cancer cells to assess the effects of baicalin on cell proliferation, migration, and invasion. The expression levels of ALOX12, reactive oxygen species (ROS), and ferroptosis markers, such as Glutathione Peroxidase 4 (GPX4) and Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4), were measured.

Baicalin treatment significantly upregulated ALOX12 expression in lung cancer cells, and this upregulation was associated with a reduction in cell proliferation, migration, and invasion. Furthermore, baicalin-induced ferroptosis was characterized by increased ROS levels, iron accumulation, and elevated expression of GPX4 and ACSL4. These findings suggest that baicalin enhances ferroptosis through ALOX12 activation, synergistically inhibiting cancer cell growth.

Baicalin significantly upregulated ALOX12 expression, promoted ferroptosis, and inhibited the proliferation and migration of A549 lung cancer cells. This finding provides evidence for the potential use of baicalin as a therapeutic agent for lung cancer and highlights the importance of ALOX12 in lung cancer treatment strategies.

The present study aimed to design and synthesize a new series of benzothiazole analogues containing 1,3,4-thiadiazole, and assess their biological activities as potential anticancer agents.

N-(5,6-dimethylbenzo[d]thiazol-2-yl)-2-((5-(substituted amino)-1,3,4-thiadiazol-2-yl)thio)acetamide derivatives (4a-4h) were synthesized via the reaction of thiadiazole derivatives (3a-3h) with 2-chloro-N-(5,6-dimethylbenzo[d]thiazol-2-yl)acetamide (1) in the presence of potassium carbonate. All the target compounds have been characterized by spectral analysis. The anticancer activities of compounds 4a-4h were tested against two human HT-1376 bladder and HT-29 colorectal carcinoma cells using the WST-1 assay. Flow cytometry was used for the determination of apoptosis, cell cycle, and caspase 3/7 activity. Moreover, wound-healing assay was utilized to evaluate cell migration. In silico physicochemical, pharmacokinetics, and toxicological properties of compound 4g were determined by pkCSM, SwissADME, and SwissTargetPrediction online web tools.

Among all synthesized derivatives, compound 4g (N-(5,6-dimethylbenzo[d]thiazol-2-yl)-2-((5-((3-methoxyphenyl)amino)-1,3,4-thiadiazol-2-yl)thio)acetamide) recorded the highest antiproliferative activity against HT-1376 cells with an IC50 as 26.51 µM at 24 h, which was less cytotoxic than cisplatin (IC50=14.85 µM). The combined treatment with compound 4g and cisplatin increased the cellular apoptosis with a higher impact compared with the cisplatin group. The higher accumulation of cells in the G2 phase, a significant increase of caspase 3/7 activity, and the inhibition of migration rate were also observed in HT-1376 following a combination of compound 4g and cisplatin treatment versus cisplatin alone, which might be involved in the apoptotic effects of compound 4g.

The in vitro anticancer potential of compound 4g lays the foundation for future research to focus on its value as a novel and advanced cancer therapy.