G. Rappa et al., REVERSAL OF ETOPOSIDE RESISTANCE IN NON-P-GLYCOPROTEIN EXPRESSING MULTIDRUG-RESISTANT TUMOR-CELL LINES BY NOVOBIOCIN, Cancer research, 53(22), 1993, pp. 5487-5493
Previous reports from this laboratory have demonstrated that novobioci
n produces supraadditive cytotoxicity and increases the formation of d
rug-stabilized topoisomerase II-DNA covalent complexes in WEHI-3B myel
omonocytic leukemia and A549 lung carcinoma cells when combined with e
toposide (VP-16). Inhibition of the efflux of VP-16 by novobiocin is r
esponsible for the increase in VP-16 accumulation, which in turn leads
to increased formation of VP-16-stabilized topoisomerase II-DNA coval
ent complexes and increased cytotoxicity. We now report that novobioci
n synergistically enhanced the sensitivity of the multidrug resistant
variants, WEHI-3B/NOVO and A549(VP)28, to VP-16, causing almost comple
te reversal of the resistance to the epipodophyllotoxin. These two tum
or cell variants are resistant to several topoisomerase II-targeted dr
ugs, particularly VP-16, but not to Vinca alkaloids; this finding corr
esponds to the fact that they do not overexpress the P-glycoprotein. T
he effects of novobiocin in these resistant sublines are mediated thro
ugh the intracellular accumulation of VP-16, resulting in an increase
in the formation of lethal VP-16-induced topoisomerase II-DNA covalent
complexes. In the P-glycoprotein expressing multidrug resistant HCT11
6(VM)34 colon carcinoma and L1210/VMDRC0.06 leukemia cell lines, the l
atter being transfected with the human mdr-1 gene, novobiocin did not
potentiate the cytotoxic activity of VP-16 nor increase the intracellu
lar accumulation of VP-16 and the formation of covalent complexes, whe
reas their normal counterparts were sensitive to the potentiating acti
vity of novobiocin when used in combination with VP-16. These results
indicate that the action of novobiocin on the intracellular transport
of VP-16 is not directed at the level of the P-glycoprotein, but that
the action of novobiocin is antagonized by the presence of the P-glyco
protein. Since novobiocin is a clinically available antibiotic, has nu
merous structural analogues available for comparative studies, and has
a relatively low toxicity profile, this drug, as well as structurally
related agents, would appear to have significant clinical potential i
n combination with an epipodophyllotoxin for the treatment of non-P-gl
ycoprotein expressing multidrug resistant tumors.