Xh. Liu et al., EFFECTS OF NORCANTHARIDIN, A PROTEIN PHOSPHATASE TYPE-2A INHIBITOR, ON THE GROWTH OF NORMAL AND MALIGNANT HEMATOPOIETIC-CELLS, European journal of cancer, 31A(6), 1995, pp. 953-963
Cantharidin is a natural toxin that inhibits protein phosphatase type
2A (PP2A) and has antitumour effects in man. We have studied the synth
etic analogue, norcantharidin (NCTD), which has less nephrotoxic and p
hlogogenic side-effects, investigating the effects on the normal haemo
poietic system and leukaemia cell growth. Daily intraperitoneal (i.p.)
injection of NCTD induced dose and circadian time-dependent transient
leucocytosis in normal mice, but did not accelerate bone marrow (BM)
regeneration, or have haemopoietic side-effects following chronic admi
nistration. NCTD stimulated the cell cycle progression of granulocyte-
macrophage colony-forming cells (GM-CFC), stimulated DNA synthesis and
increased the frequency of mitotic cells in short-term human BM cultu
res. NCTD also stimulated the production of interleukin (IL)-1 beta, c
olony stimulating activity (CSA) and tumour necrosis factor (TNF)-alph
a. Continuous in vitro NCTD treatment, however, inhibited both DNA syn
thesis and GM-CFC growth. Fluorescence-activated cell sorting (FAGS) a
nalysis of DNA profiles and cytological studies in HL-60, K-562 or MRC
5V2 (fibroblast) cells indicated that low doses of NCTD accelerated th
e G(1)/S phase transition, while higher doses or prolonged incubations
inhibited the cell cycle at the G(2)/M phases or during the formation
of postmitotic daughter cells. Electron microscopy revealed that NCTD
impaired the neogenesis of chromatin material and nuclear membrane du
ring the M/G(1) phase transition in K-562 cells. The biphasic effect o
f NCTD may be due to inhibition of PP2A activity, which regulates the
cell cycle, both at the restriction point and at the G2 and M phases.
Our data provide new insight into the cellular and molecular actions o
f NCTD, and partly explain its therapeutical effects in cancer patient
s.