Abstract
BPAP is a potent enhancer substance with catecholaminergic and serotoninergic activity in the brain. It was discovered that it is also effective against certain types of experimental cancers, showing the most promising results in case of lung cancer. That is why we tested its efficacy in two different doses in a newly developed EGFR wild type mouse lung adenocarcinoma xenograft model. Experiments were conducted on FVB/N and SCID mouse strains treated with low and high dose of BPAP. Body weight, survival, and tumor volumes were recorded. Furthermore, the activity of major signaling pathways of NSCLC such as MAPK and Akt/mTOR as well as cell cycle regulation were determined. Significant inhibition of tumor growth was exerted by both doses, but the mechanism of action was different. High dose directly inhibited, whereas low dose activated the main signaling pathways. Exposure to low dose BPAP resulted in elevated activity of the mTOR pathway together with p16INK-induced cell cycle arrest, a typical feature of geroconversion, a senescent state characterized by loss of cell proliferation. Finally the events culminated in cell cycle inhibition point in case of both doses mirrored by the decrease of cyclin D1, CDK4 and PCNA. In addition, BPAP treatment had a beneficial effect on bodyweight suggesting that the compound at least in part is able to compensate the cancer-related wasting. In view of the low toxicity and confirmed antitumor effect of BPAP against experimental lung adenocarcinoma, this novel compound deserves further attention.
Highlights
The phenethylamine derivative (−)-deprenyl gained attention in the 1970s when its ability to block MAO-B enzyme [1] was confirmed and was the first to be used in the treatment of Parkinson’s disease [2]
Experiment 1 was performed on FVB/N mice using our subcutaneous lung cancer xenograft model [12], where both low and high doses of BPAP significantly inhibited tumor growth (p < 0.05) (Fig. 1a)
The detection of targetable somatic mutations has become essential in the treatment protocol of patients with non-small cell lung cancer [19]
Summary
The phenethylamine derivative (−)-deprenyl ( known as selegiline) gained attention in the 1970s when its ability to block MAO-B enzyme [1] was confirmed and was the first to be used in the treatment of Parkinson’s disease [2]. 1 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26., Budapest H-1085, Hungary. 3 2nd Department of Pathology, Semmelweis University, Budapest, Hungary beagle dogs when given in a daily dose of 0.25 mg/kg [3,4,5]. BPAP has been shown to have neuroprotective and memory stimulatory effects similar to those of deprenyl but without the ability to inhibit the MAO-B enzyme [8]
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