Title : Anionophores, an emerging group of molecules to fight cancer
Eukaryotic life is compartmentalized and the cells have membranes separating the interior from the outside environment. Similarly, the different organelles inside cells are enclosed by membrane. Correct ion exchange through cellular membranes is an essential process for maintaining osmotic balance and intracellular pH (pHi) which are key parameters controlling many biological processes including proliferation, differentiation and apoptosis. Therefore, when cellular pH is not preserved at a favorable level, different pathologies may appear, as it is the case of cancer. Cancer cells undergo a pH deregulation during the process of carcinogenesis, resulting in the acidification of the extracellular pH and the alkalinisation of the pHi. Modulation of intracellular pH has recently been proposed as a new therapeutic strategy against cancer. Indeed, prodigiosin, a tripyrrolic natural product with anticancer properties, represents one of the first described anionophores (lipid soluble compounds that facilitate the transport of anions across cell membranes). We have been reported that its biological activity is partly due to its ability to deacidify acidic compartments within cells, which cause a drop in pHi, and therefore the onset of apoptosis described by us in a wide collection of cancer cells. Emulating that characteristic, different anionophores like obatoclax or urea /thiourea group linked to a naphthalimide compounds have been also evaluated by our research group. Recently, we have focused our attention on a novel group of anionophores named synthetic tambjamine analogues, inspired in bioactive marine alkaloids tambjamines. These compounds proved to be very efficient anion exchangers in liposome models, promoting both chloride and bicarbonate transport. We have been able to analyze in detail the molecular mechanism of cell death induced by some selected tambjamines analogues, where ROS production is related with an increased p38 kinase activity as well as a survivin down-regulation following apoptosis induction. Furthermore, we have recently shown the ability of these compounds to hyperpolarize the cellular membrane as well as differentiate and induce cell death in lung cancer stem cells, which are promising properties for their potential use in cancer therapy. Finally in collaboration with a Spanish Biotech company we have developed and assayed a drug delivery system based on innovative polyurethane/polyurea nanocapsules in order to treat more efficiently lung cancer.
This work was partially supported by a grant from the Spanish government and the EU (FIS PI13/00089) and grant from La Marató de TV3 Foundation (20132730) and grant from Junta de Castilla y León (BU09U16).