Novel Cancer Therapy: Pain Treatment Discovery (Lung, Anticancer)

Lung and Other Malignant Cancer Pain Biotherapeutics Biopharmaceuticals

Publications

Toxicon. 2008 Jan;51(1):102-11.
Inhibitory effect of crotoxin on the pain-evoked discharge of neurons in thalamic parafascicular nucleus in rats.

Department of Neurobiology, School of Medicine, Soochow University, Ren-Ai Road, Dushu Lake Campus, Suzhou Industrial Park, Suzhou 215123, PR China. Celtic Biotech, Ltd, Dublin, Ireland

Summary
Crotoxin (Cro), the principal neurotoxic component of Crotalus durissus terrificus, has been previously reported to have a behavioral analgesic effect in rats and mice. The present study investigated electrophysiologically the effect of Cro on pain-evoked unit discharge of neurons in thalamic parafascicular nucleus (Pf) and underlying mechanisms of its effect. The electrical discharge of Pf neurons was recorded with the microelectrode technique in rats. Intracerebroventricular (i.c.v.) injection of Cro at 0.25, 0.45 and 0.65 microg/kg resulted in a dose-dependent inhibitory effect on the pain-evoked discharge of Pf neurons. The discharge frequency and the discharge duration significantly (P<0.05) decreased after Cro administration. This inhibitory effect was significantly (P<0.05) attenuated after pretreatment with para-chlorophenylalanine (pCPA), or electrolytic lesion of dorsal raphe (DR) nucleus. In contrast, i.c.v. injection of atropine (muscarinic receptor antagonist, 5 microg) or naloxone (opioid receptor antagonist, 4 microg) had no effect on Cro-induced inhibition of discharge of Pf neurons. The results suggested that Cro has an analgesic effect, which is mediated, at least partially, by the central serotonergic system.

Acta Pharmacol Sin. 2007 Apr;28(4):540-8.
Autophagy is involved in cytotoxic effects of crotoxin in human breast cancer cell line MCF-7 cells

Department of Pharmacology, Soochow University School of Medicine, Suzhou 215123, China; Celtic Biotech, Ltd, Dublin, Ireland

Summary
AIM: To investigate the role of crotoxin (CrTX)-induced autophagy in the death of MCF-7 cells, a caspase-3-deficient, human breast cancer cell line. METHODS: Cultured MCF-7 cells were treated with various doses of CrTX, a phospholipase A2 (PLA2) isolated from the venom of the South American rattlesnake, Crotalus durissus terrificus. The cytotoxicity of CrTX in the presence and absence of caspase inhibitors was measured with methyl thiazolyl tetrazolium (MTT) and lactate dehydrogenase (LDH) leakage assays. The activation of autophagy was determined with transmission electron microscope and monodansylcadaverin (MDC) labeling. The upregulation of lysosomal enzymes, the release of cytochrome c (cyto-c), and the nuclear translocation of the apoptosis inducing factor (AIF) were examined by immunoblotting and immunofluorescence. RESULTS: CrTX inhibited the viability of MCF-7 cells in a dose- and time-dependent manner. CrTX-activated autophagy was revealed by punctuate MDC labeling, and an increase in the formation of autophagosomes as well as apoptosis, as evidenced by nuclear condensation and fragmentation. The activation of cathepsin B, D, and L, in addition to the release of cytochrome c and the relocation of AIF into nuclei, were observed after CrTX treatment. Autophagy inhibitors 3-methyladenine (3-MA), NH4Cl, and the pan-caspase inhibitor, Z-Val-Ala-Asp-fluoromethylketone (Z-Vad-fmk), attenuated CrTX-induced cell death. CONCLUSION: An autophagic mechanism contributes to the apoptosis of MCF-7 cells induced by CrTX.

Toxicon. 2006 Aug;48(2):175-82. Epub 2006 Apr 28.
Opiate and acetylcholine-independent analgesic actions of crotoxin isolated from crotalus durissus terrificus venom.

Department of Pharmacology, Soochow University School of Medicine, 48 Ren Ming Road, Suzhou 215007, PR China; Celtic Biotech, Ltd, Dublin, Ireland

Summary
The venom of Crotalus durissus terrificus is reported to have analgesic activity and the administration of Crotoxin (Cro) to cancer patients is reported to reduce the consumption of analgesics. This study investigated the analgesia induced by Cro and the effects of atropine and naloxone on the antinociceptive activity of Cro in mice and rats. The results showed that Cro at 66.5, 44.3 and 29.5microg/kg (ip) exhibited a dose-dependent analgesic action in mice using the hotplate and acetic acid writhing tests. Cro at 44.3microg/kg (ip) had significant analgesic action in the rat tail-flick test. In the mouse acetic acid-writhing test, intracerebral ventricular administration of Cro 0.3microg/kg produced marked analgesic effects. Microinjection of Cro (0.15microg/kg) into the periaqueductal gray area also elicited a robust analgesic action in rat hotplate test. Atropine at 0.5mg/kg (im) or 10mg/kg (ip) or naloxone at 3mg/kg (ip) failed to block the analgesic effects of Cro. These results suggest that Cro has analgesic effects mediated by an action on the central nervous system. The muscarinic and opioid receptors are not involved in the antinociceptive effects of Cro.

Toxicon. 2006 Apr;47(5):521-30. Epub 2006 Mar 15.
Contributions of autophagic and apoptotic mechanisms
to CrTX-induced death of K562 cells

Department of Pharmacology, Soochow University School of Medicine, Suzhou Institute of Chinese Materia Medica, 708 Ren Min Road, Suzhou 215007, People's Republic of China; Celtic Biotech, Ltd, Dublin, Ireland

Summary
Previous studies reported that the neurotoxin, Crotoxin, isolated from the venom of South American rattlesnake had potent anti-tumor activity. Here, we investigated the involvement of autophagy and apoptosis in the Crotoxin-induced death of chronic myeloid leukemia cell line K562 cells. The neurotoxin dose dependently inhibited the viability of K562 cells. Crotoxin stimulated the autophagic activity as evidenced by the appearance of punctuate monodansylcadaverine (MDC) fluorescence staining in the cytoplasm and increased the formation of autophagosomes. Crotoxin caused the collapse of the mitochondrial membrane potential, release of cytochrome c and activation of caspase-3. Caspase inhibitors attenuated Crotoxin-induced K562 cell death, while blockage of autophagy maturation with 3-methyladenine (3-MA) and NH4Cl potentiated the neurotoxin's cytotoxicity. These results suggest that an apoptotic mechanism contributes to the Crotoxin-induced death of K562 cells, while the activation of autophagy delays neurotoxin-induced apoptosis.

Irish Celtic Biotech Ltd. of Ireland offers drug discovery biotechnology, novel cancer therapy and pain treatment, and anticancer/antiviral oncology venom crotoxin, cardiotoxin, neurotoxins and neurological pharmaceuticals.

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