Effects of the Hedgehog pathway inhibitor GDC-0449 on lung cancer cell lines are mediated by side populations

Abstract

The hedgehog (Hh) signaling pathway has been shown to be activated in the cancer stem cells of several tumor entities. The Hh inhibitor GDC-0449 has been proven to be effective in some cancers but not yet in lung cancer. We aimed at investigating whether GDC-0449 is effective in the lung cancer cell lines HCC (adenocarcinoma) and H1339 (small-cell-lung carcinoma), whether in these cell lines stem cell-like side populations (SPs) can be identified, and whether possible effects of GDC-0449 are mediated via SPs. SPs were identified by spectrum shift and decreased fluorescence after staining with 2.5 μg/ml Hoechst 33342. Expression of proteins was quantified by immunofluorescence. GDC-0449 (25 and 50 μM) inhibited concentration-dependent cell growth in HCC and H1339 cells. Further, the inhibitory effects of cisplatin on cell growth were augmented. In HCC and H1339 cell lines, SPs of 0.57 and 0.46% could be identified, respectively. SP, but not non-SP, cells were able to repopulate the original tumor population. The Hh receptor smoothened was detectable in SP but not in non-SP cells, showing the activation of the Hh pathway only in SPs. GDC-0449 considerably reduced SPs in HCC and H1339 cells. We demonstrate for the first time that GDC-0449 effectively reduces cell growth in lung cancer cell lines. This effect is mediated by the inhibition of stem cell-like SPs.

Blockade of the sonic hedgehog pathway effectively inhibits the growth of hepatoma in mice: An in vivo study

“…These findings suggested that the hedgehog pathway was frequently activated or deregulated in human HCCs (14)(15)(16)(17)21). In vitro, certain authors considered that some hedgehog signal-responsive progenitor cells function as cancer stem cells, leading to carcinogenesis (22)(23)(24).…”

“…The third possibility affecting the level of expression of Shh pathway factors is the hypothesized concept of cancer stem cells which have the capacity of self-renewal and unlimited replication (29)(30)(31). Bailey et al also identified the so-called cancer stem cell of the pancreas (32) and Tian et al studied lung cancer and observed that the Shh pathway is activated mainly in the cancer stem cells and not in every cancer cell (23). The effect of cyclopamine upon the Shh pathway may have occurred only in the cancer stem cells of our HCC mice and not in all cancer cells.…”

Chemoresistance in Cancer Stem Cells and Strategies to Overcome Resistance

“…Another inhibitor of SMO, GDC-0449 (vismodegib, Genentech), reduced growth of several lung cancer cell lines via inhibition of the Hoescht-excluding side populations [131]. A phase I trial of GDC-0449 resulted in a number of partial and complete responses among patients with basal-cell carcinoma [132].…”

Sonic hedgehog pathway inhibitor mitigates mouse hepatocellular carcinoma

“…[29][30][31][32] GDC-0449 (vismodegib; 2-chloro-N-[4-chloro-3-pyridin-2-ylphenyl]-4-methanesulfonyl benzamide) is a potent and specific synthetic Smo inhibitor, with molecular weight 421.30 g/mol. 30,[33][34][35] Some studies reported that GDC-0449 has an antitumor activity in a mouse model of medulloblastoma and in primary human tumor cell xenograft models of colorectal cancer and pancreatic carcinoma. 30,[33][34][35] GDC-0449 treatment is effective in the advanced basal cell carcinoma animal.…”

“…30,[33][34][35] Some studies reported that GDC-0449 has an antitumor activity in a mouse model of medulloblastoma and in primary human tumor cell xenograft models of colorectal cancer and pancreatic carcinoma. 30,[33][34][35] GDC-0449 treatment is effective in the advanced basal cell carcinoma animal. 36 GDC-0449 treatment in HCC remains unclear.…”