Le chemin cellulaire NF-KB.

his certainly sounds unusual, but Dr. Son and colleagues report on the effectiveness of the snake venom toxin (SVT) Vipera lebetina turanica in the inhibition of androgen-independent prostate cancer (AICAP) in the journal Molecular Cancer Therapeutics.

Ça paraitre étrange mais le docteur Son et ses collègues rapportent l'efficacité du venin de serpent (SVT) dans l'inhibition du cancer de la prostate hormono-dépendant dans le journal : Molecular Cancer therapeuthics

The molecular focus of this report was on nuclear factor ΚB (NF- ΚB), an anti-apoptotic transcriptional factor that is constitutively activated in AICAP cell lines. The scientists showed that SVT inhibited growth of AICAP cells lines PC-3 and DU145 with IC50's of 1.7 and 1.8ug/mL, respectively. This exceeded the IC50 in LNCaP, androgen-sensitive cells (9.1ug/mL). With increasing concentrations of SVT, the number of cells distributed in the S phase of the cell cycle decreased significantly compare with cells in other phases.

Le focus du rapport est sur le facteur nucléaire KB (NF - KB), un facteur transcriptionnel anti-apoptitic qui est constamment activé dans le cancer hormono indépendant. Les scientifiques ont montré que le SVT (venin de serpent) inhibe la croissance des cellules PC-3 et DU145 avec 1.7 et 1.8 microgramme/ millilitre de IC50 respectivement.

To investigate whether SVT can inactivate NF- ΚB and thus cause cells to undergo apoptosis, PC-3 cells treated with SVT for 24 hours were assessed. The SBR interacts with NF- ΚB signal molecules by a protein-protein interaction with the cysteine residues in the NF- ΚB molecules.

Culturing the cells with SVT reduced the constitutive activation of NF- ΚB. Interaction between SSVTVT and mutant gene constructs was suggestive that the cysteine residues are the targets of SVT in the NF- ΚB molecule. Expression of cell cycle regulatory proteins was also altered in the SVT treated cells with decreased expression of G2-M phase regulation protein cyclin B1 and proteins regulating G1 phase in the cells. The increase of apoptotic action was confirmed by the induction of caspase-3 and -9 activations by SVT.
These novel findings suggest that SVT can inhibit the growth of AICAP
through the induction of cell death.

[b]Ces nouvelles découvertes suggèrent que le venin de serpent peut inhiber la croissance du cancer de la prostate hormono-indépendant à travers l'induction de la mort des cellules.[/b]

(Jun. 17, 2008) — A novel small molecule inhibitor reduced both endogenous and drug-induced resistance to chemotherapy in a mouse model of melanoma.

Une nouvelle molécule inhibitrice réduit la résistance endogène et la résistance dû aux médicaments à la chimio dans une souris avec le mélanome.

The NF-κB pathway is often active in human cancers and promotes resistance to cytotoxic chemotherapy drugs. Some cytostatic drugs, such as doxorubicin, induce NF-κB pathway activity.

Le chemin cellulaire NF-KB est souvent actif dans les cancers humains et promeut la résistance aux chimiothérapies. La doxorubicin par exemple induit l'Activité de NF-KB.

To determine if a new inhibitor of the pathway, called KINK-1, could overcome this resistance, Michael Schön, M.D., of the University Medical Center Göttingen in Germany and colleagues injected mice with melanoma cells and then treated them with doxorubicin and KINK-1.

Pour déterminer si un inhibiteur de ce chemin cellulaire (NF-KB), appelé KINK-1, pourrait venir à bout de cette résistance, des chercheurs ont injecté la doxorubicin et le KINK-1 à des souris traitées avec le mélanome.

They found that mice treated with a combination of the two drugs developed smaller lung metastases than mice treated with either agent alone.

Ils ont découvert que les souris traitées avec une combinaison des 2 médicaments ont développé des métastases plus petites qu'avec un des deux agents seuls.

"Based on our observation that the compound suppressed constitutive NF-κB activation and NF-κB activation induced by cytostatics or inflammatory agents, KINK-1 appears to be a universal inhibitor of NF-κB activation in melanoma cells, regardless of the mode of activation," the authors write.

KINK-1 apparait donc comme un agent universel de l'inhibition de NF-KB pour les cellules du mélanomes.

In an accompanying editorial, John Kirkwood, M.D., of the University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute and colleagues review the biology of NF-κB and its impact on melanoma cells. Other inhibitors of the pathway have been tried in melanoma and did not prove successful. The KINK-1 inhibitor blocks the pathway in a different manner and may have a bigger impact on the disease, though that must be tested in a clinical trail. "These new agents may be most beneficially combined with chemotherapeutic agents to which melanoma has been refractory in the past," the editorialists conclude.

L'idée que Kink-1 devrait avoir un impact important sur le cancer de la

reste à être vérifiée par des essais cliniques.

This research was recently published in the Journal of the National Cancer Institute.