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Oncogene Downregulation by Mahanine Suppresses Drug-Sensitive and Drug-Resistant Lung Cancer and Inhibits Orthotopic
Raghuram Kandimalla1,2, Disha N Moholkar1,2, Suman Kumar Samanta3
1Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
Abstract:
Background/Objectives: Lung cancer is one of the deadliest cancers, and drug resistance complicates its treatment. Mahanine (MH), an alkaloid from Murraya koenigii has been known for its anti-cancer properties. However, its effectiveness and mechanisms in treating non-small cell lung cancer (NSCLC) remain largely unexplored. The present study aimed to investigate MH's effect on drug-sensitive and drug-resistant NSCLC and its potential mechanism of action. Methods: We isolated MH from M. koenigii leaves and the purity (99%) was confirmed by HPLC, LC-MS and NMR. The antiproliferative activity of MH was determined using MTT and colony formation assays against drug-sensitive (A549 and H1299) and Taxol-resistant lung cancer cells (A549-TR). Western blot analysis was performed to determine MH's effects on various molecular targets. Anti-tumor activity of MH was determined against lung tumors developed in female NOD Scid mice injected with A549-Fluc bioluminescent cells (1.5 × 106) intrathoracically. Results: MH dose-dependently reduced the proliferation of all lung cancer cells (A549, H1299 and A549-TR), with IC50 values of 7.5, 5, and 10 µM, respectively. Mechanistically, MH arrested cell growth in the G0/G1 and G2/M phases of the cell cycle by inhibiting cyclin-dependent kinase 4/6 (CDK4/6) and cell division control 2 (CDC2) and induced apoptosis through the downregulation of B-cell leukemia/lymphoma 2 (BCL2) and B-cell lymphoma-extra large (BCL-XL). The apoptotic induction capacity of MH can also be attributed to its ability to inhibit pro-oncogenic markers, including mesenchymal-epithelial transition factor receptor (MET), phosphorylated protein kinase B (p-AKT), phosphorylated mammalian target of rapamycin (p-mTOR), survivin, rat sarcoma viral oncogene (RAS), myelocytomatosis oncogene (cMYC), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) levels. In vivo, MH (25 mg/kg b. wt.) significantly (p < 0.001) inhibited the growth of A549 lung cancer orthotopic xenografts in NOD Scid mice by 70%. Conclusions: Our study provides new mechanistic insights into MH's therapeutic potential against NSCLC.
Insights
Mahanine (MH), a natural alkaloid, shows significant anti-cancer effects against drug-sensitive and drug-resistant non-small cell lung cancer (NSCLC). This study reveals MH
Area of Science:
- Pharmacology
- Oncology
- Natural Products Chemistry
Background:
- Lung cancer remains a leading cause of cancer mortality, with drug resistance posing a significant therapeutic challenge.
- Mahanine (MH), an alkaloid derived from *Murraya koenigii*, possesses known anti-cancer properties, but its efficacy and mechanisms against non-small cell lung cancer (NSCLC) are not well understood.
Purpose of the Study:
- To investigate the anti-proliferative and anti-tumor effects of Mahanine (MH) on both drug-sensitive and drug-resistant NSCLC cell lines.
- To elucidate the underlying molecular mechanisms of MH's action in NSCLC treatment.
Main Methods:
- Mahanine (MH) was isolated from *M. koenigii* and characterized.
- In vitro antiproliferative activity was assessed using MTT and colony formation assays against A549, H1299, and A549-TR (Taxol-resistant) NSCLC cells.
- Western blot analysis was used to examine molecular targets, and in vivo anti-tumor efficacy was evaluated in an orthotopic xenograft mouse model.
Main Results:
- MH demonstrated dose-dependent inhibition of proliferation in all tested NSCLC cell lines, including drug-resistant ones.
- MH induced cell cycle arrest at G0/G1 and G2/M phases by inhibiting CDK4/6 and CDC2, and promoted apoptosis by downregulating BCL2 and BCL-XL.
- MH significantly inhibited key pro-oncogenic markers (MET, p-AKT, p-mTOR, survivin, RAS, cMYC, NF-κB) and reduced tumor growth by 70% in vivo.
Conclusions:
- Mahanine (MH) exhibits potent anti-proliferative and anti-tumor activities against non-small cell lung cancer (NSCLC), including drug-resistant forms.
- MH exerts its effects by inducing cell cycle arrest, promoting apoptosis, and inhibiting critical oncogenic signaling pathways.
- These findings highlight MH as a promising therapeutic agent for NSCLC treatment, warranting further clinical investigation.
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