Among the tested derivatives, compound B5 demonstrated the most favorable biological profile, characterized by a more pronounced biological response in HCT116 cells than in BEAS-2B cells, increased ROS generation, reduced MDM2 expression, and a marked induction of early apoptosis.
Abstract
Background/Objectives: Colorectal cancer is one of the most common malignancies worldwide and is frequently associated with dysregulation of apoptosis, oxidative stress, and the p53 regulatory axis. The development of novel compounds capable of modulating these pathways remains an important challenge in anticancer drug discovery. This study aimed to evaluate the biological activity of newly synthesized triazole–diquinothiazine derivatives in colorectal cancer cells and to identify the most promising lead compound for further development. Methods: The synthesized derivatives were evaluated in HCT116 colorectal cancer cells harboring wild-type TP53 and in normal BEAS-2B cells. Cytotoxicity, apoptosis, cell cycle distribution, intracellular reactive oxygen species (ROS) generation, and the expression of genes associated with apoptosis, oxidative stress, and inflammatory response were analyzed. Results: The investigated compounds exhibited diverse biological effects, including modulation of apoptosis, cell cycle progression, and oxidative stress. Among the tested derivatives, compound B5 demonstrated the most favorable biological profile, characterized by a more pronounced biological response in HCT116 cells than in BEAS-2B cells, increased ROS generation, reduced MDM2 expression, and a marked induction of early apoptosis. Conclusions: The obtained results indicate that triazole–diquinothiazine derivatives represent promising lead structures for further optimization. In particular, compound B5 warrants additional mechanistic and preclinical studies to evaluate its potential as a candidate for colorectal cancer therapy.
Compound 4v emerged as a leading candidate, showing EGFR kinase inhibitory activity comparable to Erlotinib, and computational analysis of 4v and EGFR molecular binding suggests that it serves as a superior binder to the inactive EGFR conformation.
Amr Elagamy, Mohamed S. Nafie, Ahmed Elnahrawy et al.· European journal of medicina...· 0 citations
Cervical cancer is the fourth most common cancer and the fourth leading cause of cancer-related mortality among women worldwide. Tangeretin (TAN), a polymethoxylated flavonoid derived from citrus fruit peel, exhibits relatively high structural stability due to its methoxy groups and exerts anticancer effects in various malignancies, including lung, liver and breast cancer. However, to the best of our knowledge, the anticancer effects of TAN in cervical cancer remain insufficiently explored. The present study investigated the mechanisms underlying the anticancer effects of TAN on the CaSki cervical cancer cell line. Cell viability was evaluated using the EZ-Cytox cell viability assay. The colony formation and cell cycle arrest assays demonstrated that TAN inhibited cell proliferation by inducing G1 phase arrest. The wound-healing and Transwell migration assays demonstrated that TAN could reduce the migratory ability of CaSki cells, and the Annexin V/propidium iodide staining assay revealed that TAN increased the apoptotic cell population. Mitochondrial reactive oxygen species (ROS) were identified using MitoSOX™ staining and the mitochondrial membrane potential (MMP) was detected using JC-1 staining. The findings of these assays suggested that TAN could increase mitochondrial ROS levels and decrease mitochondrial MMP in CaSki cells. Western blot analysis showed that TAN upregulated the protein expression levels of E-cadherin and Bax. In addition, TAN restored the tumor suppressor protein p53. Collectively, these findings suggested that may exhibit anticancer activity in CaSki cells.
Seung-Hyeon Ahn, Z. A. Bhutta, Hwayoung Na et al.· Oncology Report· 0 citations
Rosmarinic acid (RA), a naturally occurring polyphenolic compound, has attracted increasing attention because of its potential anticancer activity and capacity to modulate oxidative stress-associated signaling pathways. In the present study, the cytotoxic, apoptotic, and antiproliferative effects of RA, alone or in combination with gemcitabine (Gem), were investigated in OVCAR3 ovarian cancer cells and HaCaT keratinocytes using integrated two-dimensional and three-dimensional (3D) experimental models. Cell viability assays demonstrated dose- and time-dependent growth inhibition following RA and Gem treatment, while combination index (CI) analysis revealed synergistic cytotoxic activity in OVCAR3 cells. Flow cytometric analyses showed that combined treatment markedly increased apoptotic cell populations and altered cell cycle progression through enhanced S-phase and G2/M accumulation. Intracellular reactive oxygen species (ROS) levels were significantly elevated following combination treatment, and N-acetyl-L-cysteine (NAC) pretreatment partially attenuated both ROS accumulation and cytotoxicity, indicating a functional contribution of oxidative stress to the observed antitumor response. RT-qPCR analyses demonstrated increased expression of proapoptotic genes (BAX, CASP3, and CASP9) together with suppression of BCL2, MKI67, and CDK4 expression, while immunocytochemical analyses supported enhanced caspase-3 activation at the protein level. In 3D OVCAR3 tumor spheroids, the RA + Gem combination significantly reduced spheroid viability, disrupted spheroid architecture, and increased dead-cell accumulation compared with single-agent treatments. Collectively, these findings suggest that RA may enhance the anticancer activity of Gem in ovarian cancer cells through mechanisms associated with oxidative stress, apoptosis, and proliferation-related signaling pathways under both monolayer and 3D culture conditions.
Coşkun Orhaner, M. Tuncer, İ. Özdemir· International Journal of Mol...· 0 citations
Colorectal cancer is one of the most common malignancies worldwide and, despite recent advances in diagnosis and treatment, it remains associated with high mortality rates. Therefore, there is a growing need for novel therapeutic strategies. Medicinal plants, as natural sources of bioactive compounds, offer promising opportunities for anticancer drug development. The present study aimed to investigate the effects of
Artemisia biennis
L. on the SW480 colorectal cancer cell line and its impact on the expression of apoptosis-related genes (
BAX
and
BCL-2
) and metastasis-related genes (
MMP1
and
MMP9
). Aqueous and butanolic (polar) as well as hexane and ethyl acetate (non-polar) fractions of
A. biennis
were evaluated at different concentrations and exposure times for their effects on cell growth and viability. The results demonstrated that polar fractions, particularly the aqueous one, significantly reduced SW480 cell viability, with stronger effects observed at longer treatment durations. IC₅₀ values of the polar fractions were lower than those of non-polar fractions. Moreover,
BAX
gene expression was significantly altered in the hexane fraction, while
BCL-2
expression showed notable changes in the aqueous fraction. A decrease in
MMP1
and
MMP9
expression was also observed in the butanol and ethyl acetate fractions, suggesting reduced migratory potential
.
In line with these findings, the scratch assay showed that ethyl acetate and butanolic fractions significantly inhibited SW480 cell migration, with the butanolic fraction exerting the strongest anti-migratory effect. Overall, these findings indicate that bioactive compounds from
A. biennis
can suppress colorectal cancer cell growth through apoptosis induction and consistent with inhibition of migration-related behavior, highlighting their potential for further investigation as anticancer agents.
F. Farahani, Batoul Khafaji, Fatemeh Bidgolian et al.· BMC Cancer· 0 citations
The high mortality rate of prostate cancer remains a major threat to men's health worldwide, highlighting an urgent need for novel therapeutic agents with improved efficacy and safety profiles. In this study, we employed a rational structural modification strategy to synthesize 14 novel 1,2,3-triazole-hybridized derivatives of piperlongumine (PL), a natural alkaloid with proven anticancer activity. The antiproliferative activity of these derivatives was evaluated in vitro against multiple cancer cell lines (PC-3, A549, T47D, and SMMC-7721), with normal HEK293 cells used to assess their selectivity. All synthesized derivatives (1 M-14 M) exhibited significant antitumor efficacy, with lead compound 11 M showing pronounced inhibition of PC-3 cell proliferation and migration. Mechanistic studies revealed that 11 M induced G2/M phase arrest and triggered mitochondrial-dependent apoptosis, while concurrently activating the ROS-MAPK signaling pathway and autophagic flux. Notably, 11 M attenuated DNMT3A-mediated global DNA hypomethylation. In vivo validation in PC-3 xenograft mice confirmed that 11 M exerted robust tumor growth suppression with low systemic toxicity, accompanied by DNMT3A downregulation and MAPK pathway activation, substantiating its multi-target therapeutic mechanism.
Among the synthesized compounds, PBc1 exhibited the greatest in vitro antiproliferative activity against both MDA-MB-231 and SK-OV-3 cell lines, suggesting that PBc1 is a promising compound for further biological and mechanistic investigation.
Prachita Gauns Dessai, Parixit J. Bhandurge, C. Nazareth et al.· Journal of the Iranian Chemi...· 0 citations