The
phosphatidylinositol 3-kinase (PI3K) pathway is activated in many human
tumors and mediates processes such as cell proliferation, survival, adhesion, and motility. The
natural product,
wortmannin, has been widely used to study the functional consequences of PI3K inhibition in both normal and transformed cells in culture but is not a suitable
cancer chemotherapeutic agent due to stability and toxicity issues.
PX-866, an improved
wortmannin analogue, displays significant antitumor activity in xenograft models. Here, we directly compare
PX-866 and
wortmannin in human
cancer cell lines cultured in monolayer or as three-dimensional spheroids. Both PI3K inhibitors failed to inhibit monolayer cell growth at concentrations up to 100 nmol/L but strongly suppressed spheroid growth at low nanomolar concentrations, with
PX-866 showing greater potency than
wortmannin. Relative to
wortmannin,
PX-866 treatment results in a more sustained loss of Akt phosphorylation, suggesting that the increased potency of
PX-866 is related to a more durable inhibition of PI3K signaling.
PX-866 and
wortmannin both inhibit spheroid growth without causing cytotoxicity, similar to known
cytostatic agents, such as
rapamycin.
PX-866 also inhibits
cancer cell motility at subnanomolar concentrations. These findings suggest that the antitumor activities of
PX-866 stem from prolonged inhibition of the PI3K pathway and inhibition of cell motility. In addition, we propose that the use of three-dimensional
tumor models is more predictive of in vivo growth inhibition by PI3K inhibitors in
cancer cell lines lacking
phosphatase and
tensin homologue activity or expression.