Propranolol metabolite and enantiomers affect colorectal cancer development by inhibiting MAPK pathway and
Hanying Yi1, Yingying Dai1, Cuiyu Chen1
1Department of Clinical Pharmacology, Xiangya Hospital, Central South University, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Abstract:
Preclinical and clinical studies have demonstrated the tumor-suppressive role of propranolol, a racemic mixture that blocks β2-adrenergic receptor (β2-AR). However, the impact of 4-hydroxypropranolol, the primary metabolite of propranolol, as well as the two enantiomers of propranolol, in tumor control remains uncertain. In this study, we investigated the effects of propranolol, 4-hydroxypropranolol, and propranolol enantiomers in controlling colorectal cancer. These compounds demonstrated time- and concentration-dependent inhibition of cancer cell viability in vitro and significantly suppressed tumor growth in vivo. Notably, 4-hydroxypropranolol exhibited the most potent tumor suppressive effect among all tested compounds. Computational analyses revealed that 4-hydroxypropranolol exhibited stronger binding to β2-AR compared with propranolol (hydrogen-bond distance: 2.8 Å vs 3.1 Å). Additionally, 4-hydroxypropranolol markedly reduced the population of PD-1+CD4+T cells and PD-1+CD8+T cells in the spleen of colorectal cancer models. Furthermore, treatment with 4-hydroxypropranolol (8 mg/kg/day) significantly diminished the population of FoxP3+CD4+CD25+ T (Treg) cells in the spleens of animals, compared to the PBS group. These findings suggest that 4-hydroxypropranolol exerts a stronger tumor suppressor effect than propranolol and its enantiomers, likely due to its higher affinity for β2-AR.
Insights
4-hydroxypropranolol, a propranolol metabolite, shows stronger tumor suppression in colorectal cancer than propranolol itself. This enhanced effect is linked to its greater binding affinity to the beta-2 adrenergic receptor (β2-AR).
Area of Science:
- Pharmacology
- Oncology
- Immunology
Background:
- Propranolol, a β2-adrenergic receptor (β2-AR) blocker, has demonstrated tumor-suppressive properties.
- The specific roles of propranolol's metabolite, 4-hydroxypropranolol, and its enantiomers in tumor control are not well-established.
Purpose of the Study:
- To investigate the anti-cancer effects of propranolol, 4-hydroxypropranolol, and propranolol enantiomers on colorectal cancer.
- To compare the efficacy of these compounds in vitro and in vivo models.
- To elucidate the molecular mechanisms underlying their tumor-suppressive actions.
Main Methods:
- In vitro assessment of cancer cell viability inhibition.
- In vivo tumor growth suppression studies in colorectal cancer models.
- Computational analysis of β2-AR binding affinity.
- Flow cytometry analysis of immune cell populations (PD-1+ T cells, Treg cells) in spleen.
Main Results:
- All tested compounds inhibited cancer cell viability and suppressed tumor growth in a time- and concentration-dependent manner.
- 4-hydroxypropranolol demonstrated the most potent tumor suppressive effect.
- Computational analysis indicated higher binding affinity of 4-hydroxypropranolol to β2-AR compared to propranolol.
- 4-hydroxypropranolol significantly reduced PD-1+ CD4+ T cells, PD-1+ CD8+ T cells, and FoxP3+ CD4+ CD25+ regulatory T cells (Tregs) in spleen.
Conclusions:
- 4-hydroxypropranolol exhibits superior tumor suppressor activity against colorectal cancer compared to propranolol and its enantiomers.
- The enhanced efficacy of 4-hydroxypropranolol is likely attributed to its increased binding affinity for the β2-AR.
- These findings highlight the potential of 4-hydroxypropranolol as a therapeutic agent in colorectal cancer treatment.
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