Ganetespib with Methotrexate Acts Synergistically to Impede NF-κB/p65 Signaling in Human Lung Cancer A549 Cells
Among the various types of cancer, lung cancer accounts for the highest number of fatalities across the globe. A combination of different cancer chemotherapeutics is regarded as an effective strategy for clinical management of different cancers. Ganetespib (GAN) is a well-established hsp90 inhibitor with enhanced pharmacological properties in comparison with its first-generation counterparts. Previous preclinical studies have shown that GAN exerts significant effects against cancer cells; however, its therapeutic effects against non-small cell lung cancer (NSCLC) A549 cells, achieved by modulating the expression of the NF-κB/p65 signaling pathway, remains unexplored. In this study, the combinatorial effect of GAN and methotrexate (MTX) against lung carcinomas was investigated through both in silico and in vitro studies. A combinatorial treatment regimen of GAN/MTX exerted more significant cytotoxic effects (p < 0.001) against A549 cells than individual treatments. The GAN/MTX combination also instigated nuclear fragmentation followed by augmentation in intracellular ROS levels (p < 0.001). The elevated ROS in A549 cells upon exposure to GAN/MTX combinatorial regimen was concomitantly accompanied with a remarkable reduction in mitochondrial viability. In addition, it was observed that the GAN/MTX combination succeeded in elevating caspase-3 activity and downregulating the expression levels of anti-apoptotic mediators Bcl2 and survivin in NSCLC A549 cells. Most importantly, the GAN/MTX combinatorial regimen impeded the activation of the NF-kB/p65 signaling pathway via repression of the expression of E-cadherin and N-cadherin, which was confirmed by molecular docking studies. Collectively, these findings demonstrated the synergistic effect of the GAN/MTX combinatorial regimen in suppressing the growth of A549 cells by modulating the NF-κB/p65 signaling pathway.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:16 |
|---|---|
| Enthalten in: |
Pharmaceuticals (Basel, Switzerland) - 16(2023), 2 vom: 02. Feb. |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Subaiea, Gehad [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Anticancer |
|---|
| Anmerkungen: |
Date Revised 03.06.2023 published: Electronic Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.3390/ph16020230 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM357614887 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM357614887 | ||
| 003 | DE-627 | ||
| 005 | 20231226072955.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.3390/ph16020230 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1191.xml |
| 035 | |a (DE-627)NLM357614887 | ||
| 035 | |a (NLM)37259378 | ||
| 035 | |a (PII)230 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Subaiea, Gehad |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Ganetespib with Methotrexate Acts Synergistically to Impede NF-κB/p65 Signaling in Human Lung Cancer A549 Cells |
| 264 | 1 | |c 2023 | |
| 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 Revised 03.06.2023 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a Among the various types of cancer, lung cancer accounts for the highest number of fatalities across the globe. A combination of different cancer chemotherapeutics is regarded as an effective strategy for clinical management of different cancers. Ganetespib (GAN) is a well-established hsp90 inhibitor with enhanced pharmacological properties in comparison with its first-generation counterparts. Previous preclinical studies have shown that GAN exerts significant effects against cancer cells; however, its therapeutic effects against non-small cell lung cancer (NSCLC) A549 cells, achieved by modulating the expression of the NF-κB/p65 signaling pathway, remains unexplored. In this study, the combinatorial effect of GAN and methotrexate (MTX) against lung carcinomas was investigated through both in silico and in vitro studies. A combinatorial treatment regimen of GAN/MTX exerted more significant cytotoxic effects (p < 0.001) against A549 cells than individual treatments. The GAN/MTX combination also instigated nuclear fragmentation followed by augmentation in intracellular ROS levels (p < 0.001). The elevated ROS in A549 cells upon exposure to GAN/MTX combinatorial regimen was concomitantly accompanied with a remarkable reduction in mitochondrial viability. In addition, it was observed that the GAN/MTX combination succeeded in elevating caspase-3 activity and downregulating the expression levels of anti-apoptotic mediators Bcl2 and survivin in NSCLC A549 cells. Most importantly, the GAN/MTX combinatorial regimen impeded the activation of the NF-kB/p65 signaling pathway via repression of the expression of E-cadherin and N-cadherin, which was confirmed by molecular docking studies. Collectively, these findings demonstrated the synergistic effect of the GAN/MTX combinatorial regimen in suppressing the growth of A549 cells by modulating the NF-κB/p65 signaling pathway | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a NF-κB/p65 signaling | |
| 650 | 4 | |a NSCLC | |
| 650 | 4 | |a anticancer | |
| 650 | 4 | |a ganetespib | |
| 650 | 4 | |a lung cancer | |
| 650 | 4 | |a methotrexate | |
| 700 | 1 | |a Rizvi, Syed Mohd Danish |e verfasserin |4 aut | |
| 700 | 1 | |a Yadav, Hemant Kumar Singh |e verfasserin |4 aut | |
| 700 | 1 | |a Al Hagbani, Turki |e verfasserin |4 aut | |
| 700 | 1 | |a Abdallah, Marwa Helmy |e verfasserin |4 aut | |
| 700 | 1 | |a Khafagy, El-Sayed |e verfasserin |4 aut | |
| 700 | 1 | |a Gangadharappa, Hosahalli Veerabhadrappa |e verfasserin |4 aut | |
| 700 | 1 | |a Hussain, Talib |e verfasserin |4 aut | |
| 700 | 1 | |a Abu Lila, Amr Selim |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Pharmaceuticals (Basel, Switzerland) |d 2009 |g 16(2023), 2 vom: 02. Feb. |w (DE-627)NLM199619514 |x 1424-8247 |7 nnns |
| 773 | 1 | 8 | |g volume:16 |g year:2023 |g number:2 |g day:02 |g month:02 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.3390/ph16020230 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 16 |j 2023 |e 2 |b 02 |c 02 | ||