Novel furan chalcone modulates PHD-2 induction to impart antineoplastic effect in mammary gland carcinoma
© 2024 Wiley Periodicals LLC..
Normoxic inactivation of prolyl hydroxylase-2 (PHD-2) in tumour microenvironment paves the way for cancer cells to thrive under the influence of HIF-1α and NF-κB. Henceforth, the present study is aimed to identify small molecule activators of PHD-2. A virtual screening was conducted on a library consisting of 265,242 chemical compounds, with the objective of identifying molecules that exhibit structural similarities to the furan chalcone scaffold. Further, PHD-2 activation potential of screened compound was determined using in vitro 2-oxoglutarate assay. The cytotoxic activity and apoptotic potential of screened compound was determined using various staining techniques, including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, 4',6-diamidino-2-phenylindole (DAPI), 1,1',3,3'-tetraethylbenzimi-dazolylcarbocyanine iodide (JC-1), and acridine orange/ethidium bromide (AO/EB), against MCF-7 cells. 7,12-Dimethylbenz[a]anthracene (DMBA) model of mammary gland cancer was used to study the in vivo antineoplastic efficacy of screened compound. [(E)-1-(4-fluorophenyl)-3-(furan-2-yl) prop-2-en-1-one] (BBAP-7) was screened and validated as a PHD-2 activator by an in vitro 2-oxo-glutarate assay. The IC50 of BBAP-7 on MCF-7 cells is 18.84 µM. AO/EB and DAPI staining showed nuclear fragmentation, blebbing and condensation in MCF-7 cells following BBAP-7 treatment. The red-to-green intensity ratio of JC-1 stained MCF-7 cells decreased after BBAP-7 treatment, indicating mitochondrial-mediated apoptosis. DMBA caused mammary gland dysplasia, duct hyperplasia and ductal carcinoma in situ. Carmine staining, histopathology, and scanning electron microscopy demonstrated that BBAP-7, alone or with tirapazamine, restored mammary gland surface morphology and structural integrity. Additionally, BBAP-7 therapy significantly reduced oxidative stress and glycolysis. The findings reveal that BBAP-7 activates PHD-2, making it a promising anticancer drug.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2024 |
---|---|
Erschienen: |
2024 |
Enthalten in: |
Zur Gesamtaufnahme - volume:38 |
---|---|
Enthalten in: |
Journal of biochemical and molecular toxicology - 38(2024), 4 vom: 15. März, Seite e23679 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Rastogi, Shubham [VerfasserIn] |
---|
Links: |
---|
Anmerkungen: |
Date Completed 18.03.2024 Date Revised 18.03.2024 published: Print Citation Status MEDLINE |
---|
doi: |
10.1002/jbt.23679 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM369760972 |
---|
LEADER | 01000caa a22002652 4500 | ||
---|---|---|---|
001 | NLM369760972 | ||
003 | DE-627 | ||
005 | 20240318234823.0 | ||
007 | cr uuu---uuuuu | ||
008 | 240315s2024 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1002/jbt.23679 |2 doi | |
028 | 5 | 2 | |a pubmed24n1335.xml |
035 | |a (DE-627)NLM369760972 | ||
035 | |a (NLM)38486411 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Rastogi, Shubham |e verfasserin |4 aut | |
245 | 1 | 0 | |a Novel furan chalcone modulates PHD-2 induction to impart antineoplastic effect in mammary gland carcinoma |
264 | 1 | |c 2024 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 18.03.2024 | ||
500 | |a Date Revised 18.03.2024 | ||
500 | |a published: Print | ||
500 | |a Citation Status MEDLINE | ||
520 | |a © 2024 Wiley Periodicals LLC. | ||
520 | |a Normoxic inactivation of prolyl hydroxylase-2 (PHD-2) in tumour microenvironment paves the way for cancer cells to thrive under the influence of HIF-1α and NF-κB. Henceforth, the present study is aimed to identify small molecule activators of PHD-2. A virtual screening was conducted on a library consisting of 265,242 chemical compounds, with the objective of identifying molecules that exhibit structural similarities to the furan chalcone scaffold. Further, PHD-2 activation potential of screened compound was determined using in vitro 2-oxoglutarate assay. The cytotoxic activity and apoptotic potential of screened compound was determined using various staining techniques, including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, 4',6-diamidino-2-phenylindole (DAPI), 1,1',3,3'-tetraethylbenzimi-dazolylcarbocyanine iodide (JC-1), and acridine orange/ethidium bromide (AO/EB), against MCF-7 cells. 7,12-Dimethylbenz[a]anthracene (DMBA) model of mammary gland cancer was used to study the in vivo antineoplastic efficacy of screened compound. [(E)-1-(4-fluorophenyl)-3-(furan-2-yl) prop-2-en-1-one] (BBAP-7) was screened and validated as a PHD-2 activator by an in vitro 2-oxo-glutarate assay. The IC50 of BBAP-7 on MCF-7 cells is 18.84 µM. AO/EB and DAPI staining showed nuclear fragmentation, blebbing and condensation in MCF-7 cells following BBAP-7 treatment. The red-to-green intensity ratio of JC-1 stained MCF-7 cells decreased after BBAP-7 treatment, indicating mitochondrial-mediated apoptosis. DMBA caused mammary gland dysplasia, duct hyperplasia and ductal carcinoma in situ. Carmine staining, histopathology, and scanning electron microscopy demonstrated that BBAP-7, alone or with tirapazamine, restored mammary gland surface morphology and structural integrity. Additionally, BBAP-7 therapy significantly reduced oxidative stress and glycolysis. The findings reveal that BBAP-7 activates PHD-2, making it a promising anticancer drug | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a DMBA | |
650 | 4 | |a MCF-7 | |
650 | 4 | |a PHD-2 activator | |
650 | 4 | |a breast cancer | |
650 | 4 | |a hypoxia | |
650 | 7 | |a Prolyl Hydroxylases |2 NLM | |
650 | 7 | |a EC 1.14.11.- |2 NLM | |
650 | 7 | |a Chalcones |2 NLM | |
650 | 7 | |a 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine |2 NLM | |
650 | 7 | |a 21527-78-6 |2 NLM | |
650 | 7 | |a Antineoplastic Agents |2 NLM | |
650 | 7 | |a Acridine Orange |2 NLM | |
650 | 7 | |a F30N4O6XVV |2 NLM | |
650 | 7 | |a Chalcone |2 NLM | |
650 | 7 | |a 5S5A2Q39HX |2 NLM | |
650 | 7 | |a Benzimidazoles |2 NLM | |
650 | 7 | |a Carbocyanines |2 NLM | |
700 | 1 | |a Ansari, Mohd Nazam |e verfasserin |4 aut | |
700 | 1 | |a Saeedan, Abdulaziz S |e verfasserin |4 aut | |
700 | 1 | |a Singh, Sunil Kumar |e verfasserin |4 aut | |
700 | 1 | |a Mukerjee, Alok |e verfasserin |4 aut | |
700 | 1 | |a Kaithwas, Gaurav |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Journal of biochemical and molecular toxicology |d 1998 |g 38(2024), 4 vom: 15. März, Seite e23679 |w (DE-627)NLM093581521 |x 1099-0461 |7 nnns |
773 | 1 | 8 | |g volume:38 |g year:2024 |g number:4 |g day:15 |g month:03 |g pages:e23679 |
856 | 4 | 0 | |u http://dx.doi.org/10.1002/jbt.23679 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 38 |j 2024 |e 4 |b 15 |c 03 |h e23679 |