3-Pyridinylidene Derivatives of Chemically Modified Lupane and Ursane Triterpenes as Promising Anticancer Agents by Targeting Apoptosis

Казакова, О. Б.; Èoica, CodruÈa; Бабаев, М. С.; Petrova, А. V.; Khusnutdinova, É. F.; Poptsov, A. I.; MacaÈoi, Ioana; Drăghici, George Andrei; Avram, Ștefana; Vlaia, Lavinia; Mioc, Alexandra; Mioc, Marius; Dehelean, Cristina; Voicu, Adrian

doi:10.3390/ijms221910695

Cited by 11 publications

(5 citation statements)

References 79 publications

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“…BA exhibited the same previously reported effect correlated with BCL2/BAX gene modulation on A375 melanoma cells, with quantitative results similar to other studies where PCR was used to determine BCL-2/BAX relative fold gene expression [60]. This pattern extends to other BA derivatives that were designed by chemical modulations of various positions (3-OH, 28-COOH or 30-allyl) [61][62][63] that in some cases led to a slight modification of the triterpene core as well [64]. This collectively suggests that the hydrophobic triterpene scaffold is essential for the alteration of the Bcl-2/BAX normal ratio.…”

Section: Discussionsupporting

confidence: 84%

Exploring the Antimelanoma Potential of Betulinic Acid Esters and Their Liposomal Nanoformulations

Milan,

Mioc,

Mioc

et al. 2024

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Betulinic acid is a naturally occurring pentacyclic triterpene belonging to the lupane-group that exhibits a wide range of pharmacological activities. BA derivatives are continuously being researched due to their improved anticancer efficacy and bioavailability. The current research was conducted in order to determine the antiproliferative potential of three synthesized BA fatty esters using palmitic, stearic and butyric acids and their liposomal nanoformulations. The cytotoxic potential of BA fatty esters (Pal-BA, St-BA, But-BA) and their respective liposomal formulations (Pal-BA-Lip, St-BA-Lip, But-BA-Lip) has been assessed on HaCaT immortalized human keratinocytes and A375 human melanoma cells. Both the esters and their liposomes acted as cytotoxic agents against melanoma cells in a time- and dose-dependent manner. The butyryl ester But-BA outperformed BA in terms of cytotoxicity (IC50 60.77 μM) while the nanoformulations St-BA-Lip, But-BA-Lip and BA-Lip also displayed IC50 values (60.11, 50.71 and 59.01 μM) lower compared to BA (IC50 65.9 μM). The morphological evaluation revealed that the A375 cells underwent morphological changes consistent with apoptosis following 48 h treatment with the tested compounds, while the HaCaT cells’ morphology remained unaltered. Both the esters and their liposomal formulations were able to inhibit the migration of the melanoma cells, suggesting a significant antimetastatic effect. The quantitative real-time PCR revealed that all tested samples were able to significantly increase the expression of the pro-apoptotic Bax and inhibit the anti-apoptotic Bcl-2 proteins. This effect was more potent in the case of liposomal nanoformulations versus non-encapsulated compounds, and overall, But-BA and its formulation exhibited the best results in this regard.

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Section: Discussionsupporting

confidence: 84%

Exploring the Antimelanoma Potential of Betulinic Acid Esters and Their Liposomal Nanoformulations

Milan,

Mioc,

Mioc

et al. 2024

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“…The molecular docking protocol used in our current work was previously described [ 57 , 58 ]. The protein target structure of Bcl-2 (PDB ID: 2W3L) was obtained from the RCSB Protein Data Bank [ 59 ].…”

Section: Methodsmentioning

confidence: 99%

Novel Triterpenic Acid—Benzotriazole Esters Act as Pro-Apoptotic Antimelanoma Agents

Mioc

Prodea

et al. 2022

IJMS

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Pentacyclic triterpenes, such as betulinic, ursolic, and oleanolic acids are efficient and selective anticancer agents whose underlying mechanisms of action have been widely investigated. The introduction of N-bearing heterocycles (e.g., triazoles) into the structures of natural compounds (particularly pentacyclic triterpenes) has yielded semisynthetic derivatives with increased antiproliferative potential as opposed to unmodified starting compounds. In this work, we report the synthesis and biological assessment of benzotriazole esters of betulinic acid (BA), oleanolic acid (OA), and ursolic acid (UA) (compounds 1–3). The esters were obtained in moderate yields (28–42%). All three compounds showed dose-dependent reductions in cell viability against A375 melanoma cells and no cytotoxic effects against healthy human keratinocytes. The morphology analysis of treated cells showed characteristic apoptotic changes consisting of nuclear shrinkage, condensation, fragmentation, and cellular membrane disruption. rtPCR analysis reinforced the proapoptotic evidence, showing a reduction in anti-apoptotic Bcl-2 expression and upregulation of the pro-apoptotic Bax. High-resolution respirometry studies showed that all three compounds were able to significantly inhibit mitochondrial function. Molecular docking showed that compounds 1–3 showed an increase in binding affinity against Bcl-2 as opposed to BA, OA, and UA and similar binding patterns compared to known Bcl-2 inhibitors.

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“…The DNA damage reveals the nuclear modification in apoptosis and it was examined by a DAPI DNA binding assay [74]. A549 cells (1.5 × 105 cells/well) were pretreated with CLX 5 µM or not and incubated with and without OT 25 µM for 12 h. After incubation, treated cells were fixed in formaldehyde (4%) in PBS for 10 min.…”

Section: 6-diamidino-2-phenylindole Dihydrochloride (Dapi) Stainingmentioning

confidence: 99%

Orientin, a Bio-Flavonoid from Trigonella hamosa L., Regulates COX-2/PGE-2 in A549 Cell Lines via miR-26b and miR-146a

et al. 2022

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Cancer is a severe health condition and considered one of the major healthcare issues and is in need of innovative strategy for a cure. The current study aimed to investigate the chemical profile of Trigonella hamosa L. and a potential molecular approach to explain its regulation in cancer progression through an inflammatory mediator (COX-2) in A549 non-small lung cancer cell lines via in silico, mechanistic and molecular aspects. T. hamosa was extracted and then subjected to a CCK-8 cell viability assay in different cancer cell lines including MDA-MB-231, A549 and HCT-116. Total extract was subjected to several chromatographic techniques to yield orientin (OT); the structure was elucidated by inspection of NMR spectroscopic data. To achieve anticancer effects of OT, a cell viability assay using a CCK-8 kit, immunoprecipitation by Western blot, cell migration using a wound healing assay, cell invasion using a Matrigel-Transwell assay, apoptosis by AO/EB dual staining, flow cytometric analysis and DAPI staining, a silenced COX-2 model to determine PGE-2 production and real-time PCR and Western blot of BCL-2, CYP-1A1, iNOS and COX-2 markers were carried out. The results demonstrated that OT decreased the cell proliferation and controlled cell migration and invasive properties. OT destabilized the COX-2 mRNA and downregulated its expression in A549 cell lines. Virtual binding showed interaction (binding energy −10.43) between OT and COX-2 protein compared to the selective COX-2 inhibitor celecoxib (CLX) (binding energy −9.4). The OT-CLX combination showed a superior anticancer effect. The synergistic effect of OT-CLX combination was noticed in controlling the migration and invasion of A549 cell lines. OT-CLX downregulated the expression of BCL-2, iNOS and COX-2 and activated the proapoptotic gene CYP-1A1. OT mitigated the COX-2 expression via upregulation of miR-26b and miR-146a. Interestingly, COX-2-silenced transfected A549 cells exhibited reduced expression of miR-26b and miR-146a. The findings confirmed the direct interaction of OT with COX-2 protein. PGE-2 expression was quantified in both naïve and COX-2-silenced A549 cells. OT downregulated the release of PGE-2 in both tested conditions. These results confirmed the regulatory effect of OT on A549 cell growth in a COX-2-dependent manner. OT activated apoptosis via activation of CYP-1A1 expression in an independent manner. These results revealed that the OT-CLX combination could serve as a potential synergistic treatment for effective inflammatory-mediated anticancer strategies.

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3-Pyridinylidene Derivatives of Chemically Modified Lupane and Ursane Triterpenes as Promising Anticancer Agents by Targeting Apoptosis

Cited by 11 publications

References 79 publications

Exploring the Antimelanoma Potential of Betulinic Acid Esters and Their Liposomal Nanoformulations

Exploring the Antimelanoma Potential of Betulinic Acid Esters and Their Liposomal Nanoformulations

Novel Triterpenic Acid—Benzotriazole Esters Act as Pro-Apoptotic Antimelanoma Agents

Orientin, a Bio-Flavonoid from Trigonella hamosa L., Regulates COX-2/PGE-2 in A549 Cell Lines via miR-26b and miR-146a

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