Signal pathways involved in apigenin inhibition of growth and induction ofapoptosis of human anaplastic thyroid cancer cells (ARO)

Recently we demonstrated that several flavonoids can inhibit the proliferat ion of certain human thyroid cancel cell lines. Among the flavonoids tested apigenin and luteolin are the most effective inhibitors of these tumor cel l lines. In the present study, we investigated the signal transduction mech anism associated with the growth inhibitory effect of apigenin, using a hum an anaplastic thyroid carcinoma cell line, ARO (UCLA RO-81-A-1). Using West ern blot method, it was shown that the inhibitory effect of apigenin on ARO cell proliferation is associated with an inhibition of both EGFR tyrosine autophosphorylation and phosphorylation of its downstream effector mitogen activated protein (MAP) kinase. Protein levels of these signaling molecules were not affected. The inhibition of phosphorylation by apigenin occurred within 30 min and continued for 4 h. A dose-dependent inhibition was demons trable ranging from 12.5 mu M to 50 mu M. The level of phosphorylated c-Myc , a nuclear substrate for MAPK, was depressed from 16-48 h after apigenin t reatment, finally leading to a programmed cell death involving DNA fragment ation. Furthermore, treatment with apigenin resulted in the inhibition of b oth anchorage-dependent and anchorage-independent thyroid cancel cell growt h. In summary, apigenin is a promising inhibitor of signal transduction pat hways that regulate the growth (anchorage-dependent and independent) and su rvival of human anaplastic thyroid cancer cells. Apigenin may provide a new approach for the treatment of human anaplastic thyroid carcinoma for which no effective therapy is presently available.