Author/Editor		Pilkington, Geoffrey J; Akinwunmi, James; Amar, Sabrina
Title		The role of tricyclic drugs in selective triggering of mitochondrially-mediated apoptosis in neoplastic glia: a therapeutic option in malignant glioma?
Translated title		Pomen tricikličnih zdravil pri selektivnem proženju mitohondrijske apoptoze pri neoplastični gliji. Nova možnost zdravljenja malignih gliomov?
Type		članek
Source		Radiol Oncol
Vol. and No.		Letnik 40, št. 2
Publication year		2006
Volume		str. 73-85
Language		eng
Abstract		We have previously demonstrated that the tricyclic antidepressant, Clomipramine, exerts a concentration - dependent, tumor cell specific, pro-apoptotic effect on human glioma cells in vitro and than this effect is not mirrored in non-neoplastic human astrocytes. Moreover, the drug acts by triggering mitochondrially-mediated apoptosis by way of complex 3 of the respiratory chain. Here, through reduced reactive oxygen species and neoplastic cell specific, altered membrane potential, cytochrome c is released, thereby activating a caspase pathway to apoptosis. In addition, while we and others have shown that further antidepressants, including those of the selective serotonin reuptake inhibitor (SSRI) group, also mediate cancer cell apoptosis in both glioma and lymphoma, clomipramine appears to be most effective in this context. More recently, other groups have reported that clomipramine causes apoptosis, preceded by a rapid increase in p-c-Jun levels, cytochrome c release from mitochondria and increased caspase-3 like activity. In addition to clomipramine we have investigated the possible pro-apoptotic activity of a range of further tricyclic drugs. Only two such agents (amitriptyline and doxepin) showed a similar, or better, effect when compared with clomipramine. Since both orally administered clomipramine and amitriptyline are metabolised to desmethly clomipramine (norclomipramine) and nortriptyline respectively it is necessary for testing at a tumour cell level to be carried out with both the parent tricyclic and the metabolic product. In addition, reversal of multidrug resistance in a number of solid cancers following treatment with both clomipramine and amitriptyline has been reported. This additional role for tricyclics may be of some significance in the treatment of primary and secondary brain tumours. (Abstract truncated at 2000 characters)
Summary		Izhodišča. Naše raziskave so že pokazale, da ima triciklični antidepresiv klomipramin in vitro specifičen pro-apoptotičen učinek na humanih malignih gliomskih celicah. Učinek je odvisen od koncentracije klomipramina in ga ni opaziti na normalnih humanih astrocitih. Zdravilo sproža apoptozo tako, da deluje na mitohondrije, kjer učinkuje na dihalno verigo. Ceprav so ob naših tudi druge raziskave pokazale, da imajo različni antidepresivi (vključno s selektivnimi zaviralci ponovnega prevzema serotonina - SSRI) vpliv na apoptozo pri limfomih in gliomih, je klomipramin najbolj učinkovit. Ugotavljali smo tudi pro-apoptotično aktivnost drugih tricikličnih zdravil in odkrili, da imata le dve takšni zdravili (amitriptilin in doksepin) enako ali boljšo učinkovitost kot klomipramin. Per os zaužiti zdravili klomipramin in amitriptilin se metabolizirata v desmetil klomipramin (norklomipramin) in nortriptilin. Menimo, da bi bilo potrebno testirati tumorske celice na omenjeni zdravili in na njuna metabolita. Učinkovitost obeh zdravil je namreč lahko močno zmanjšana zaradi odpornosti na zdravila (multidrug resistance), ki pa je pri obeh zdravilih različna. Ugotovili smo tudi, da ima metabolit klomipramina norklomipramin slabši pro-apoptotični učinek, medtem ko ima metabolit amitriptina nortriptilin enak učinek kot amitriptin. Zaključki. Menimo, da bo potrebno v kliničnih raziskavah ugotoviti učinkovitost tricikličnih antidepresivov pri malignem gliomu, najprej kot dopolnilno zdravljenje.
Descriptors		BRAIN NEOPLASMS GLIOMA APOPTOSIS CLOMIPRAMINE ANTIDEPRESSIVE AGENTS, TRICYCLIC