APS12-2 is a synthetic analog of the toxic, biologically active polymeric alkylpyridinium salts (poly-APS) isolated from the marine sponge Reniera sarai. In vitro, APS12-2 is capable of inducing cell death of non-small cell lung cancer (NSCLC) cells in micro-molar concentrations. Since it is potentially interesting candidate for lung cancer treatment, its possible toxic and lethal effects in vivo were studied. Arterial blood pressure (aBP), electrocardiograms (ECG), and respiratory activity were recorded in anesthetized untreated, artificially ventilated, and atropine-pretreated rats injected with APS12-2. Administration of APS12-2 at a dose of 8 mg/kg caused a progressive fall of aBP to a mid-circulatory value. Arrhythmias developed including bradycardia, ventricular extrasystoles, and atrio-ventricular conduction block of second degree. Similar results in ECG and aBP caused by APS12-2 (8 mg/kg) were observed in animals pretreated with atropine, and in artificially ventilated animals, revealing that hypoxia and cholinergic effects do not play a key role in the toxicity of APS12-2. APS12-2 at sublethal doses (4 and 5.5 mg/kg) caused a significant transient decrease of aBP. We found that APS12-2 causes lysis of rat erythrocytes in vitro and in vivo. Hyperkalemia was measured in the blood of experimental animals, and probably plays an important role in APS12-2 cardiotoxicity. This is supported by histopathology of the heart where no evident lesions were found. Acute lesions were observed in the pulmonary vessels of rats after application of 8 mg/kg APS12-2. Major effects were dilation of interalveolar blood vessels and lysis of aggregated erythrocytes within their lumina.
B.03 Paper at an international scientific conference
COBISS.SI-ID: 3405946We have shown that APS8 inhibits α7 nAChRs indicating that it is a strong α7 nAChRs antagonist and can thus induce tumor regression. APS8 has significant selective cytotoxicity towards NSCLC cells while has no influence on normal lung fibroblast cells MRC5. Evidence of apoptosis activation by APS8 in NSCLC was quantitatively analyzed by annexin V-FITC/propidium iodide uptake analysis with fluorescent cytometry. Cell morphology of APS8 induced apoptosis was investigated with a combination of the fluorescent DNA-binding dyes acridine orange and ethidium bromide. We investigated mechanism underlying the apoptotic activity of APS8. Traetment of NSCLC with APS8 upregulates proapoptotic proteins from Bcl-2 family while anti-apoptotic proteins are down-regulated. APS8 markedly increased the expression levels of death receptors. Our results imply that both intrinsic and extrinsic pathway of apoptosis are activated by APS8. Apoptosis of cancer cells induced with nAChR antagonist APS8 may be a new and promising method in lung cancer treatment.
B.03 Paper at an international scientific conference
One of the therapeutical approaches against cancer is to use drugs enhancing cell death and blocking cell proliferation of cancer cells. α7 nAChR antagonists (α-bungarotoxin or methyllycaconitine) can attenuate the proliferative effects of agonists like nicotine. We have shown that synthetic analogues of poly-APS have high affinity for nAChRs. They inhibit alpha α7 nAChRs with concentration as low as 0.1 ng/ml and are therefore strong antagonists of α7 nAChR. A synthetic analogue APS8 shows a significant toxicity towards NSCLC (A549 cell line). It inhibits tumor cell growth in a concentration dependent manner. As a control we tested the effect of APS8 on normal lung fibroblast cells (MRC5) which did not show alterations in growth until high concentrations of APS8 were used.
B.03 Paper at an international scientific conference