Combinatory lung tumor inhibition by myo-inositol and iloprost/rapamycin: association with immunomodulation
Fekadu Kassie1,2, Alireza Jian Bagherpoor1, Katalin Kovacs2
1Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
Abstract:
Although both preclinical and clinical studies have suggested that myo-inositol (MI) may be a safe and effective lung cancer chemopreventive agent, its efficacy is moderate. To test whether the chemopreventive agents iloprost (IL) or rapamycin enhance the lung tumor inhibitory effects of MI, A/J mice were treated with the tobacco smoke carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and, beginning one week after the end of NNK treatment, given MI, IL, rapamycin, MI + IL or MI + rapamycin for 17 weeks. Analyses of the number and size of tumors on the surface of the lung have indicated that MI, IL, rapamycin, MI + IL and MI + rapamycin reduced the multiplicity of NNK-induced lung tumors by 41, 34, 46, 79 and 67%, respectively, and larger tumors (lung tumors with a diameter of 1-2 or >2 mm) were absent in the MI + IL and MI + rapamycin groups. These results clearly indicated that MI + IL and MI + rapamycin are more effective than MI alone in inhibiting the formation and growth of lung tumors. Assessment of the immunomodulatory effects of the drugs showed that whereas MI + rapamycin and MI + IL increased the infiltration of lung tumors by CD4+ and CD8+ T cells, MI + rapamycin reduced the expression of the immune checkpoint protein programmed-death ligand-1 (PD-L1). Moreover, all treatments, except IL, increased apoptosis, whereas cell proliferation was markedly suppressed in all treated groups. In summary, these results suggest that IL and rapamycin could enhance the efficacy of MI in lung cancer chemoprevention trials.
Insights
Myo-inositol (MI) combined with iloprost (IL) or rapamycin significantly enhances lung cancer chemoprevention by reducing tumor multiplicity and growth. These combinations also modulate immune responses within lung tumors, suggesting improved therapeutic potential.
Area of Science:
- Oncology
- Pharmacology
- Immunology
Background:
- Preclinical and clinical studies suggest myo-inositol (MI) as a potential lung cancer chemopreventive agent.
- The efficacy of myo-inositol (MI) as a standalone lung cancer chemopreventive agent is moderate.
- Investigating synergistic effects of other agents with MI is crucial for enhancing lung cancer chemoprevention.
Purpose of the Study:
- To evaluate if iloprost (IL) or rapamycin can enhance the lung tumor inhibitory effects of myo-inositol (MI).
- To assess the impact of combined MI, IL, and rapamycin treatments on NNK-induced lung tumors in A/J mice.
- To investigate the immunomodulatory effects of these combined treatments on lung tumors.
Main Methods:
- A/J mice were exposed to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco smoke carcinogen.
- Mice received treatments including myo-inositol (MI), iloprost (IL), rapamycin, MI + IL, or MI + rapamycin for 17 weeks.
- Tumor multiplicity, size, immune cell infiltration (CD4+, CD8+ T cells), PD-L1 expression, apoptosis, and cell proliferation were analyzed.
Main Results:
- MI, IL, and rapamycin alone reduced NNK-induced lung tumor multiplicity by 41%, 34%, and 46%, respectively.
- Combinations of MI + IL and MI + rapamycin demonstrated significantly higher efficacy, reducing tumor multiplicity by 79% and 67%, respectively.
- Larger tumors were absent in the MI + IL and MI + rapamycin groups, which also showed increased T cell infiltration and, in the case of MI + rapamycin, reduced PD-L1 expression.
Conclusions:
- Combined treatment with myo-inositol (MI) and either iloprost (IL) or rapamycin significantly enhances lung tumor inhibition compared to MI alone.
- These combination therapies show potential for improving lung cancer chemoprevention strategies.
- The enhanced efficacy is associated with increased T cell infiltration and modulation of immune checkpoints and cell proliferation/apoptosis.
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