Manumycin Enhances the Cytotoxic Effect of Paclitaxel on Anaplastic Thyroid Carcinoma Cells
2000
Despite the current multimodal approach to treatment of anaplastic
thyroid cancer (ATC), the prognosis for patients with the disease is
poor. New effective therapy for ATC is desperately needed. Thus, we
investigated the effects of manumycin (a farnesyl:protein transferase
inhibitor), alone and in combination with other drugs frequently used
to treat ATC, in six human ATC cell lines: ARO, C643, DRO, Hth-74,
KAT-4, and KAT-18. By means of a formazan dye-based spectrophotometric
assay of cell viability and light microscopy, manumycin was shown to
decrease the number of viable cells in all six of the cell lines though
to a lesser degree in DRO and C643 cells than in ARO, Hth-74, KAT-4,
and KAT-18 cells. In combination, manumycin enhanced the effect of
paclitaxel in all six of the cell lines. The mechanism of cell death
was investigated by measuring caspase-3 activity, immunoblotting with
anti-poly-(ADP-ribose)polymerase (PARP) antibody and electrophoresis of
DNA. After an 18-h incubation, manumycin plus paclitaxel caused
enhanced activation of caspase-3 activity, cleavage of PARP into
M r 89,000 and 28,000 fragments, and
internucleosomal fragmentation of DNA (all of which are characteristic
of apoptotic cell death). In contrast, neither manumycin alone,
paclitaxel alone, doxorubicin alone, nor doxorubicin plus manumycin
produced significant specific cleavage of PARP and internucleosomal DNA
fragmentation after 18 h of incubation. The in vivo
effect and toxicity of combined manumycin and paclitaxel treatments
were evaluated in a nude mouse xenograft model using ARO and KAT-4
cells. Drugs were injected i.p. on days 1 and 3 of a 7-day cycle for
three cycles. Both manumycin (7.5 mg/kg/dose) and paclitaxel (20
mg/kg/dose) had significant inhibitory effects on tumor growth.
Combined manumycin and paclitaxel treatments seemed as effective as
manumycin against ARO cells and more effective than either manumycin or
paclitaxel alone against KAT-4 cells. No significant morbidity or
mortality was caused by the treatments. In conclusion, manumycin can
inhibit the growth of ATC both in vitro and in
vivo . Manumycin plus paclitaxel has enhanced cytotoxic effects
and increased apoptotic cell death in ATC cells in vitro
compared with either drug by itself. The combination of manumycin and
paclitaxel is also effective in vivo with no significant
toxicity observed. The lack of synergy observed in this in
vivo experiment may be due to a ceiling effect, and further
experimentation is warranted to ascertain the optimal way to combine
these two agents for maximal therapeutic effects.
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