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GANT61/BI-847325 combination: a new hope in lung cancer treatment
Abdel Halim M El-Kishky1, Nermine Moussa2, Maged W Helmy3
1Department of Biotechnology, Institute of Graduate Studies and Research, Alexandria University, Alexandria, Egypt.
Abstract:
Despite the huge efforts employed to implement novel chemotherapeutic paradigms for lung cancer, the disease still remains a major concern worldwide. Targeting molecular pathways as Hedgehog (Hh) and Mitogen-activated protein kinase (MAPK) represent a new hope in lung cancer treatment. This work was undertaken to evaluate the antitumor effects of GANT61 (5 μM), BI-847325(30 μM), and GANT61 (5 μM)/BI-847325(30 μM) combination on A549 adenocarcinoma lung cancer cell line. The growth inhibition 50 (GI50) for both drugs was performed using MTT. The protein levels of Caspase-3, Bcl-2-associated X protein (Bax), Myeloid cell leukemia sequence 1 (MCL-1), cyclin D1, vascular endothelial growth factor (VEGF), extracellular signal-regulated kinases (ERK), p-Akt, and phosphohistone H3 (pHH3) were measured using ELISA. Glioma-associated oncogene homolog 1(Gli1) gene expression was assessed by quantitative real-time PCR. The GI50 for GANT61 and BI-8473255 were 5 µM and 30 µM, respectively. Caspase-3 and Bax protein levels were significantly elevated while MCL-1, cyclin D1, VEGF, ERK 1/2, p-Akt, and pHH3 levels were significantly reduced by both drugs and their combination relative to the control group. Gli1 gene expression was down-regulated in all groups relative to the control group. GANT61, BI-847325 and their combination inhibited proliferation and angiogenesis but activated the apoptotic pathway. Both drugs conferred a profound negative impact on the crosstalk between each of Hh and MAPK pathways and Phosphoinositide 3 -kinases (PI3K)/Akt/Mammalian target of Rapamycin (mTOR). To the best of our knowledge, the antitumor effects of BI-847325/GANT61 combination have not been tested before. Further in-vitro and in-vivo studies are warranted to support the findings.
Insights
This study shows that GANT61 and BI-847325 drugs, alone or combined, effectively inhibit lung cancer cell growth by activating apoptosis and reducing proliferation and angiogenesis. These findings offer new hope for lung cancer treatment targeting Hedgehog (Hh) and Mitogen-activated protein kinase (MAPK) pathways.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Lung cancer remains a significant global health concern despite advancements in chemotherapy.
- Targeting molecular pathways such as Hedgehog (Hh) and Mitogen-activated protein kinase (MAPK) presents a promising therapeutic strategy.
- The specific combination of GANT61 and BI-847325 for lung cancer treatment has not been previously investigated.
Purpose of the Study:
- To evaluate the antitumor effects of GANT61 and BI-847325, individually and in combination, on the A549 lung adenocarcinoma cell line.
- To assess the impact of these agents on key molecular pathways involved in cancer cell proliferation, apoptosis, and angiogenesis.
- To investigate the modulation of Glioma-associated oncogene homolog 1 (Gli1) gene expression and its role in the observed antitumor effects.
Main Methods:
- Cell viability was assessed using MTT assays to determine the growth inhibition 50 (GI50) values for GANT61 and BI-847325.
- Protein levels of apoptosis markers (Caspase-3, Bax, MCL-1), cell cycle regulators (cyclin D1), angiogenesis factors (VEGF), and signaling pathway components (ERK, p-Akt, pHH3) were quantified using ELISA.
- Quantitative real-time PCR was employed to measure Glioma-associated oncogene homolog 1 (Gli1) gene expression.
Main Results:
- GANT61 exhibited a GI50 of 5 μM, while BI-847325 had a GI50 of 30 μM.
- Both drugs and their combination significantly increased Caspase-3 and Bax protein levels, indicating apoptosis induction.
- A significant reduction in MCL-1, cyclin D1, VEGF, ERK1/2, p-Akt, and pHH3 levels was observed, alongside down-regulation of Gli1 gene expression, suggesting inhibition of proliferation and angiogenesis.
Conclusions:
- GANT61 and BI-847325, both individually and in combination, demonstrate significant antitumor activity against A549 lung cancer cells.
- The observed effects are mediated through the activation of apoptotic pathways and the inhibition of proliferation and angiogenesis.
- These findings highlight the potential of targeting Hh and MAPK pathways, and their crosstalk with PI3K/Akt/mTOR, for novel lung cancer therapeutics, warranting further investigation.
