Rapamycin Potentiates Transforming Growth Factor β-Induced Growth Arrest in Nontransformed, Oncogene-Transformed, and Human Cancer Cells

Defective TGF-β signaling sensitizes human cancer cells to rapamycin

“…As shown in Figure 1a, rapamycin treatment of MDA-MB-231 cells in the presence of serum resulted in an increase in the percentage of cells with a G 1 DNA content and a reduction of cells with greater than G 1 DNA content. These data are consistent with those reported by Law et al (2002), where they also observed that rapamycin causes cells to accumulate in G 1 . Their data revealed a more significant accumulation in G 1 , which was likely due to a 24-h treatment rather than the 18-h treatment used here.…”

“…TGF-b suppresses rapamycin-induced apoptosis N Gadir et al synergistically to induce G 1 arrest in MDA-MB-231 cells (Law et al, 2002). Their data and ours indicate that whereas TGF-b by itself was unable to induce cell cycle arrest in MDA-MB-231 cells, rapamycin and TGF-b together did induce G 1 cell cycle arrest (Law et al, 2002).…”

“…A potential complication in the use of rapamycin in anti-cancer therapies is that in many cases, the effect of rapamycin is cytostatic and does not kill cancer cells (Neshat et al, 2001;Podsypanina et al, 2001;Law et al, 2002). We reported previously that under conditions of serum withdrawal, rapamycin induces apoptosis in MDA-MB-231 breast cancer cells (Chen et al, 2005).…”

“…Serum is a complex mixture of growth factors; however, if the effect is due to suppression of cell cycle progression, then a serum factor capable of suppressing cell cycle progression could be implicated. We therefore examined the effect of TGF-b, which can suppress cell cycle progression (Law et al, 2002;Siegel and Massague, 2003) on the ability of rapamycin to induce apoptosis in serum-starved MDA-MB-231 cells. As demonstrated previously (Chen et al, 2005) and indicated in Figure 1a, there is a large loss in cell viability in MDA-MB-231 cells subjected to serum withdrawal in the presence of rapamycin (Figure 1b).…”

“…Although there have been some successes, clinical trials with rapamycin and rapamycin derivatives such as CCI-779 and RAD-001 have been largely disappointing (Sawyers, 2003;Guertin and Sabatini, 2005). One of the problems with the use of rapamycin as an anti-cancer drug is that in most cases, rapamycin is cytostatic rather than cytotoxic and induces G 1 cell cycle arrest, rather than apoptosis (Neshat et al, 2001;Podsypanina et al, 2001;Law et al, 2002).…”