nucleotide phosphodiesterases (PDEs) comprise a family of related proteins,
which can be subdivided into 11 families (PDE1-PDE11) based on their amino acid sequences;
sensitivity to different activators
and inhibitors; and their ability
to preferentially hydrolyze either cAMP,
cGMP, or both cAMP and cGMP 1. cAMP- and cGMP-signalling regulate vast number of physiological
processes, including, visual transduction, cell proliferation, differentiation,
Inflammation apoptosis, glycogen
synthesis, glycogenolysis, lipogenesis and lipolysis 1. Rotlerin or mallotoxin is the main
constituent of phloroglucinol powder extracted from kamala tree 2, 3 . Many studies in past have shown
that biological effect of Rotlerin involves PKC-delta. Recent studies refute
this claim 4. Soltoof et al., showed that
rotlerin is an uncoupler of mitochondrial respiration and mimic effects caused
by direct PKC-delta inhibition 5, 6. Schluter et al., (1995)
showed that in heart parathyroid hormone activates PKC; activated PKC
stimulates PDE’S depleting cAMP within cells 7.
AMPK is activated in cells under
cell stress conditions (which deplete cellular ATP levels and increase cellular
cAMP levels) like glucose stavation and hypoxia, 8, 9. Park et al., reported that resveratol
is a non-specific PDE inhibitor inhibiting PDE1, PDE3 and PDE4 but not PDE2 or
PDE5. Perk et al., also reported that resveratol activates pAMPK by inhibition
of PDE’S 10 . Lentini A et al.,
1998 showed that theophylline and
caffeine non selective pde
inhibitors inhibit cell proliferation and metastasis of melanoma
Marko Drees et al., 1998 observed that Pde4 Iinhibitor DC-TA-46 inhibits proliferation of MCF-7 breast cancer cells and melanoma cells 12
. Joseph et al 2000 repoted that PDE5 and PDE2 inhibitor Sulindac sulfone
(exisulind) induced apoptosis in SW480 and HT29 cells 13.
Marika et al.,
2003 showed that PDE5 inhibitors induced apoptosis in B-CLL cells by caspase activation 14.
Mechanism involved in the
biological effect of rotlerin is still unclear. Song et al., 2008 reported that
apoptosis and autophagy induced by rotlerin in
HT1080 cancer cells
is not dependent on PKC-delta. 15.Singh et al., 2012 observed no
effect on rotlerin induced autophagy by genetic knockdown of PKC-deta in pancreatic cancer
stem cells 16.
Our report that rotlerin is a PDE inhibitor may help in understanding
its mechanism in a better way.