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Understanding cytotoxicity induction by plumbagin in pancreatic ductal adenocarcinoma using network pharmacology,
Shruti Gupta1,2, Khushhal Rathore1, Kiran Kumar Tejavath1,3
1Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, NH-8, Bandarsindri, 305817 Ajmer, Rajasthan India.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is a cancer with a very poor prognosis, which is bolstered by its resistance and pathogenesis. Quest for PDAC treatments has not left any stones unturned. A well-known naphthoquinone found in many foods, plumbagin (PLGN) demonstrated effectiveness in treating cancer, arthritis, dysmenorrhea, and injuries. We hypothesize therapeutic advantages of PLGN in PDAC and used web resources to assist us identify the targets of PLGN in order to test the idea. After that, in-vitro studies were carried out to comprehend PLGN impacts on two PDAC cell lines. Further, drug combination with PLGN and pre-sensitization by PLGN was also carried out. Findings from network pharmacology investigations revealed PLGN's targets in PDAC, indicating effect on PDAC survival by targeting crucial signalling. In-vitro tests demonstrated dose-dependent cytotoxicity of PLGN, with IC50 values for Panc-1 and Mia-PaCa-2 cells after 48 h were 2.89 ± 0.42µM and 13.10 ± 0.76µM, respectively. Dox-PLGN and Gem-PLGN combination treatment had antagonistic effects, although doxorubicin's impact was amplified by PLGN pre-sensitization. The EMT transition and genes that cause resistance were the primary pathways impacted by PLGN therapy that enhance Dox effect. Analysis of gene expression and ROS production demonstrated that PLGN had a different effect on both cell lines. Overall, PLGN shows promise as a pre-sensitizing natural substance for PDAC treatment, promoting more research on its effectiveness, tolerability, and possible incorporation into current chemotherapy regimens.
Supplementary Information:
The online version contains supplementary material available at 10.1007/s10616-026-00912-0.
Insights
Plumbagin (PLGN), a natural compound, shows promise in treating pancreatic ductal adenocarcinoma (PDAC). It exhibits cytotoxicity and enhances chemotherapy effectiveness by targeting key survival pathways and overcoming drug resistance.
Area of Science:
- Oncology
- Pharmacology
- Natural Products Chemistry
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited treatment options due to inherent resistance.
- Plumbagin (PLGN), a naphthoquinone found in various foods, has demonstrated anti-cancer properties.
- Investigating PLGN's therapeutic potential in PDAC is crucial for developing novel treatment strategies.
Purpose of the Study:
- To explore the therapeutic advantages of plumbagin (PLGN) in pancreatic ductal adenocarcinoma (PDAC).
- To identify PLGN's molecular targets in PDAC using network pharmacology.
- To evaluate the in-vitro efficacy of PLGN, alone and in combination, on PDAC cell lines.
Main Methods:
- Network pharmacology analysis to predict PLGN targets in PDAC.
- In-vitro cytotoxicity assays on Panc-1 and Mia-PaCa-2 cell lines.
- Drug combination studies and pre-sensitization experiments with doxorubicin and gemcitabine.
Main Results:
- Network pharmacology identified crucial signaling pathways targeted by PLGN, impacting PDAC survival.
- PLGN demonstrated dose-dependent cytotoxicity against PDAC cell lines, with IC50 values of 2.89µM (Panc-1) and 13.10µM (Mia-PaCa-2) after 48h.
- PLGN pre-sensitization enhanced doxorubicin efficacy by targeting EMT and resistance pathways, while combinations with doxorubicin and gemcitabine showed antagonism.
Conclusions:
- Plumbagin (PLGN) exhibits significant anti-PDAC potential by targeting critical survival and resistance pathways.
- PLGN acts as a promising pre-sensitizing agent, enhancing the effectiveness of conventional chemotherapy.
- Further research into PLGN's tolerability and integration into PDAC treatment regimens is warranted.
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