Jatrophane diterpenes and cancer multidrug resistance - ABCB1 efflux modulation and selective cell death induction
Mariana Alves Reis1, Omar Bauomy Ahmed2, Gabriella Spengler3
1Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Avenue Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
Background:
Modulation of P-glycoprotein (ABCB1) and evaluation of the collateral sensitivity effect are among the most promising approaches to overcome multidrug resistance (MDR) in cancer. In a previous study, two rare 12,17-cyclojatrophanes (1-2) and other novel jatrophanes (3-4), isolated from Euphorbia welwitschii, were screened for collateral sensitivity effect. Herein, the isolation of another jatrophane (5) is presented, being the broader goal of this work to investigate the role of euphowelwitschines A (1) and B (2), welwitschene (3), epoxywelwitschene (4) and esulatin M (5) as ABCB1 modulators and/or collateral sensitivity agents.
Methods:
Compounds 1-5 were evaluated for ABCB1 modulation ability through combination of transport and chemosensitivity assays, using a mouse T-lymphoma MDR1-transfected cell model. Moreover, the nature of interaction of compound 4 with ABCB1 was studied, using an ATPase assay. The MDR-selective antiproliferative activity of compound 5 was evaluated against gastric (EPG85-257) and pancreatic (EPP85-181) human cancer cells and their drug-selected counterparts (EPG85-257RDB, EPG85-257RNOV, EPP85-181RDB, EPP85-181RNOV). The drug induced cell death was investigated for compounds 4 and 5, using the annexin V/PI staining and the active caspase-3 assay.
Results:
The jatrophanes 1-5 were able to modulate the efflux activity of ABCB1, and at 2µM, 3-5 maintained the strong modulator profile. Structure activity results indicated that high conformational flexibility of the twelve-membered ring of compounds 3-5 favored ABCB1 modulation, in contrast to the tetracyclic scaffold of compounds 1 and 2. The effects of epoxywelwitschene (4) on the ATPase activity of ABCB1 showed it to interact with the transporter and to be able to reduce the transport of a second subtrate. Drug combination experiments also corroborated the anti-MDR potential of these diterpenes due to their synergistic interaction with doxorubicin (combination index <0.7). Esulatin M (5) showed a strong MDR-selective antiproliferative activity against EPG85-257RDB and EPP85-181RDB cells, with IC50 of 1.8 and 4.8 µM, respectively. Compounds 4 and 5 induced apoptosis via caspase-3 activation. A significant discrimination was observed between the resistant cell lines and parental cells.
Conclusions:
This study strengthens the role of jatrophane diterpenes as lead candidates for the development of MDR reversal agents, higlighting the action of compounds 4 and 5.
Insights
Jatrophane diterpenes, including epoxywelwitschene (4) and esulatin M (5), show potential in overcoming multidrug resistance (MDR) by modulating P-glycoprotein (ABCB1). These compounds exhibit MDR-selective activity and induce apoptosis, strengthening their role as lead candidates for MDR reversal agents.
Area of Science:
- Natural Products Chemistry
- Cancer Pharmacology
- Molecular Biology
Background:
- Multidrug resistance (MDR) in cancer poses a significant challenge, with P-glycoprotein (ABCB1) modulation and collateral sensitivity being key strategies.
- Previous research identified novel jatrophanes from Euphorbia welwitschii with potential anti-cancer properties.
- This study focuses on further investigating specific jatrophanes for their ability to overcome MDR.
Purpose of the Study:
- To investigate the role of euphowelwitschines A (1) and B (2), welwitschene (3), epoxywelwitschene (4), and esulatin M (5) as ABCB1 modulators.
- To evaluate their potential as collateral sensitivity agents in overcoming MDR.
- To assess their MDR-selective antiproliferative activity and mechanisms of cell death induction.
Main Methods:
- Compounds 1-5 were tested for ABCB1 modulation using transport and chemosensitivity assays in a MDR1-transfected cell model.
- ATPase assays were used to study the interaction of compound 4 with ABCB1.
- Antiproliferative activity of compound 5 was evaluated against human gastric and pancreatic cancer cells and their resistant counterparts.
- Apoptosis induction was assessed using annexin V/PI staining and active caspase-3 assays.
Main Results:
- Jatrophanes 1-5 modulated ABCB1 efflux activity, with compounds 3-5 showing strong modulation at 2µM.
- Conformational flexibility of the twelve-membered ring in compounds 3-5 correlated with enhanced ABCB1 modulation.
- Epoxywelwitschene (4) interacted with ABCB1 and reduced substrate transport; compounds 3-5 showed synergistic effects with doxorubicin.
- Esulatin M (5) exhibited potent MDR-selective antiproliferative activity against resistant gastric and pancreatic cancer cells.
- Compounds 4 and 5 induced apoptosis via caspase-3 activation, demonstrating discrimination between resistant and parental cells.
Conclusions:
- Jatrophane diterpenes, particularly compounds 4 and 5, are promising lead candidates for developing agents to reverse MDR.
- Their ability to modulate ABCB1 and induce apoptosis highlights their therapeutic potential in overcoming cancer drug resistance.
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