Exploring MTH1 inhibitory potential of Thymoquinone and Baicalin for therapeutic targeting of breast cancer
Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved..
Cancers frequently have increased ROS levels due to disrupted redox balance, leading to oxidative DNA and protein damage, mutations, and apoptosis. The MTH1 protein plays a crucial role by sanitizing the oxidized dNTP pools. Hence, cancer cells rely on MTH1 to prevent the integration of oxidized dNTPs into DNA, preventing DNA damage and allowing cancer cell proliferation. We have discovered Thymoquinone (TQ) and Baicalin (BC) as inhibitors of MTH1 using combined docking and MD simulation approaches complemented by experimental validations via assessing binding affinity and enzyme inhibition. Docking and MD simulations studies revealed an efficient binding of TQ and BC to the active site pocket of the MTH1, and the resultant complexes are appreciably stable. Fluorescence measurements estimated a strong binding affinity of TQ and BC with Ka 3.4 ×106 and 1.0 ×105, respectively. Treating breast cancer cells with TQ and BC significantly inhibited the growth and proliferation (IC50 values 28.3 µM and 34.8 µM) and induced apoptosis. TQ and BC increased the ROS production in MCF7 cells, imposing substantial oxidative stress on cancer cells and leading to cell death. Finally, TQ and BC are proven strong MTH1 inhibitors, offering promising prospects for anti-cancer therapy.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:173 |
|---|---|
| Enthalten in: |
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie - 173(2024) vom: 01. März, Seite 116332 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Taiyab, Aaliya [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 27.03.2024 Date Revised 27.03.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.biopha.2024.116332 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM369205057 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM369205057 | ||
| 003 | DE-627 | ||
| 005 | 20240328000004.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240304s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.biopha.2024.116332 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1351.xml |
| 035 | |a (DE-627)NLM369205057 | ||
| 035 | |a (NLM)38430630 | ||
| 035 | |a (PII)S0753-3322(24)00216-6 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Taiyab, Aaliya |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Exploring MTH1 inhibitory potential of Thymoquinone and Baicalin for therapeutic targeting of breast cancer |
| 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 27.03.2024 | ||
| 500 | |a Date Revised 27.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved. | ||
| 520 | |a Cancers frequently have increased ROS levels due to disrupted redox balance, leading to oxidative DNA and protein damage, mutations, and apoptosis. The MTH1 protein plays a crucial role by sanitizing the oxidized dNTP pools. Hence, cancer cells rely on MTH1 to prevent the integration of oxidized dNTPs into DNA, preventing DNA damage and allowing cancer cell proliferation. We have discovered Thymoquinone (TQ) and Baicalin (BC) as inhibitors of MTH1 using combined docking and MD simulation approaches complemented by experimental validations via assessing binding affinity and enzyme inhibition. Docking and MD simulations studies revealed an efficient binding of TQ and BC to the active site pocket of the MTH1, and the resultant complexes are appreciably stable. Fluorescence measurements estimated a strong binding affinity of TQ and BC with Ka 3.4 ×106 and 1.0 ×105, respectively. Treating breast cancer cells with TQ and BC significantly inhibited the growth and proliferation (IC50 values 28.3 µM and 34.8 µM) and induced apoptosis. TQ and BC increased the ROS production in MCF7 cells, imposing substantial oxidative stress on cancer cells and leading to cell death. Finally, TQ and BC are proven strong MTH1 inhibitors, offering promising prospects for anti-cancer therapy | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Breast cancer, MD simulation | |
| 650 | 4 | |a Cancer therapy | |
| 650 | 4 | |a Drug discovery | |
| 650 | 4 | |a MTH1 enzyme | |
| 650 | 4 | |a Molecular docking | |
| 650 | 4 | |a Natural products | |
| 650 | 7 | |a thymoquinone |2 NLM | |
| 650 | 7 | |a O60IE26NUF |2 NLM | |
| 650 | 7 | |a baicalin |2 NLM | |
| 650 | 7 | |a 347Q89U4M5 |2 NLM | |
| 650 | 7 | |a Reactive Oxygen Species |2 NLM | |
| 650 | 7 | |a Benzoquinones |2 NLM | |
| 650 | 7 | |a Nucleotides |2 NLM | |
| 650 | 7 | |a DNA |2 NLM | |
| 650 | 7 | |a 9007-49-2 |2 NLM | |
| 650 | 7 | |a Phosphoric Monoester Hydrolases |2 NLM | |
| 650 | 7 | |a EC 3.1.3.2 |2 NLM | |
| 650 | 7 | |a Flavonoids |2 NLM | |
| 700 | 1 | |a Choudhury, Arunabh |e verfasserin |4 aut | |
| 700 | 1 | |a Haidar, Shaista |e verfasserin |4 aut | |
| 700 | 1 | |a Yousuf, Mohd |e verfasserin |4 aut | |
| 700 | 1 | |a Rathi, Aanchal |e verfasserin |4 aut | |
| 700 | 1 | |a Koul, Priyanka |e verfasserin |4 aut | |
| 700 | 1 | |a Chakrabarty, Anindita |e verfasserin |4 aut | |
| 700 | 1 | |a Islam, Asimul |e verfasserin |4 aut | |
| 700 | 1 | |a Shamsi, Anas |e verfasserin |4 aut | |
| 700 | 1 | |a Hassan, Md Imtaiyaz |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie |d 1984 |g 173(2024) vom: 01. März, Seite 116332 |w (DE-627)NLM012645591 |x 1950-6007 |7 nnns |
| 773 | 1 | 8 | |g volume:173 |g year:2024 |g day:01 |g month:03 |g pages:116332 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.biopha.2024.116332 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 173 |j 2024 |b 01 |c 03 |h 116332 | ||