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Self-Assembled Maslinic Acid Attenuates Doxorobucin Induced Cytotoxicity via Nrf2 Signaling Pathway: An In Vitro and
Jhimli Banerjee1, Sk Nurul Hasan2, Sovan Samanta1
1Department of Physiology, University of Gour Banga, Malda, West Bengal, 732103, India.
Abstract:
The clinical applications of some well-known chemotherapeutic drugs for cancer treatment have been restricted nowadays owing to their adverse effects on many physiological systems. In this experimental study, maslinic acid (MA) isolated from Olea europaea (Olive) fruit extract was used to mitigate the cytotoxicity induced by Doxorubicin (DOX) in human healthy peripheral blood mononuclear cells (hPBMCs). Self-assembled maslinic acid (SA-MA) was obtained in ethanol-water mixture (35.5 mM: 4:1 v/v). The morphology of SA-MA was analyzed by various physicochemical characterization techniques, which revealed its micro-metric vesicular architecture as well as nano-vesicular appearances. In this study, treatment of hPBMCs with DOX has been found to generate severe intracellular oxidative stress, which was significantly mitigated after pre-treatment with SA-MA. Alteration of hPBMC morphologies after DOX treatment was also restored notably by pre-treatment with SA-MA. Furthermore, pentoxifylline (TNF-α inhibitor) and indomethacin (COX-2 inhibitor) were used to investigate the responsible pathway by which SA-MA protected hPBMCs from DOX-induced cellular stress. Restoration of hPBMC viability above 92% in both cases confirmed that SA-MA protected the cells by inhibiting inflammatory pathways generated by DOX treatment. Subsequently, in molecular docking study, it was also evaluated that MA could successfully bind with the pocket region of Keap1, while Nrf2 was capable of upregulating cytoprotecting genes.
Insights
Maslinic acid (MA) protects healthy cells from chemotherapy damage. Self-assembled maslinic acid (SA-MA) mitigated Doxorubicin (DOX)-induced oxidative stress and inflammation in human cells, preserving cell viability.
Area of Science:
- Pharmacology
- Cell Biology
- Natural Products Chemistry
Background:
- Chemotherapeutic drugs like Doxorubicin (DOX) can cause significant side effects, limiting their clinical use.
- Maslinic acid (MA), a natural compound from Olea europaea, is explored for its potential protective properties.
- Human peripheral blood mononuclear cells (hPBMCs) are utilized to study drug-induced cytotoxicity.
Purpose of the Study:
- To investigate the protective effects of self-assembled maslinic acid (SA-MA) against Doxorubicin (DOX)-induced cytotoxicity in hPBMCs.
- To elucidate the mechanisms underlying SA-MA's protective action, including its impact on oxidative stress and inflammatory pathways.
- To evaluate the binding potential of maslinic acid (MA) with key proteins involved in cellular protection.
Main Methods:
- Preparation and physicochemical characterization of self-assembled maslinic acid (SA-MA).
- Treatment of hPBMCs with DOX and SA-MA, followed by assessment of oxidative stress, cell morphology, and viability.
- Inhibition assays using pentoxifylline (TNF-α inhibitor) and indomethacin (COX-2 inhibitor) to identify protective pathways.
- Molecular docking studies to assess the binding affinity of MA to Keap1 and its interaction with Nrf2.
Main Results:
- SA-MA exhibited vesicular architecture at micro- and nano-metric scales.
- SA-MA significantly mitigated DOX-induced intracellular oxidative stress and restored hPBMC morphology.
- hPBMC viability was preserved above 92% when SA-MA inhibited inflammatory pathways (TNF-α and COX-2).
- Molecular docking indicated MA binds to Keap1, potentially activating Nrf2-mediated cytoprotective gene expression.
Conclusions:
- SA-MA effectively protects hPBMCs from DOX-induced cytotoxicity by reducing oxidative stress.
- The protective mechanism involves the inhibition of inflammatory pathways, specifically those involving TNF-α and COX-2.
- MA's interaction with the Keap1-Nrf2 pathway suggests a role in upregulating cellular defense mechanisms against chemotherapy-induced damage.
