K. Dimas et al., Labdane type diterpenes down-regulate the expression of c-Myc protein, butnot of Bcl-2, in human leukemia T-cells undergoing apoptosis, LEUK RES, 25(6), 2001, pp. 449-454
Sclareol (1) and ent-3 beta -hydroxy-13-epi-manoyl oxide (2) belong to the
labdane type diterpenes. They were isolated from the leaves and from the fr
uits of Cistus creticus subsp. creticus, and were found to be active agains
t human leukemic cell lines. Compound 2 was converted to its thiomidazolide
derivative (3). Compounds I and 3 were found to induce apoptotic cell deat
h in human T cell leukemia lines and to interfere with their cell cycle, ar
resting cells at G(0/1) phase. Apoptosis can involve the activation and/or
suppression of critical genes such as c-myc whose reduction or its inapprop
riate expression can be associated with induction of cell death and bcl-2 w
hose activation prevents apoptosis in the latter case. In order to detect a
ny concomitant effect (1 and 3) upon c-myc and bcl-2 oncogene expression, w
e performed Western blot analysis to determine the levels of expression of
these two genes upon treatment with the above compounds. Western blot analy
sis showed that of c-myc proto-oncogene levels were markedly reduced before
massive apoptosis ensued in H33AJ-JA1 and MOLT3 cells, while bcl-2 express
ion remained unaffected. Thus, induction of apoptosis due to compounds I an
d 3 in these T cell leukemic cell lines is preceded by c-myc down regulatio
n and furthermore sustained bcl-2 expression does not rescue cells from apo
ptosis under the conditions used. (C) 2001 Elsevier Science Ltd. All rights
reserved.