Smoothened antagonist GDC-0449 (Vismodegib) inhibits proliferation and triggers apoptosis in colon cancer cell lines

Abstract

Abstract. The sonic hedgehog (Shh) pathway has been proven to be involved in embryonic development and cancer growth. GDC-0449, an antagonist of the hedgehog signaling receptor Smoothened (Smo), was recently approved by the US Food and Drug Administration as a prescription for skin basal cell carcinoma. However, the efficacy of GDC-0449 in the treatment of colon cancer and other malignancies, such as basal cell carcinoma and pancreatic cancer, has remained to be proven. The present study assessed the effect of GDC-0449 on the colon cancer cell lines Caco-2 and Ht-29. A Cell Counting Kit-8 assay was applied to assess the cell proliferation rate and apoptosis was tested by flow cytometry. Reverse-transcription quantitative PCR and western blot analysis were used for analyzing expression levels of target genes. Cell proliferation was inhibited, while apoptosis was increased by GDC-0449, whereas the expression of B-cell lymphoma 2 (Bcl-2), a downstream target of Shh signaling, was decreased. Consistent with the inhibition of Gli1 expression, the cancer stem cell markers CD44 and ALDH were decreased in the presence of GDC-0449. In conclusion, GDC-0449 was shown to inhibit the replication of colon cancer cells and trigger apoptosis through downregulating Bcl-2. This may also influence the stemness of cancer stem cells as indicated by the decreased stem cell surface markers.

Radiation Sensitization of Basal Cell and Head and Neck Squamous Cell Carcinoma by the Hedgehog Pathway Inhibitor Vismodegib

“…In more detail, vismodegib-mediated Hh inhibition significantly decreased the number of viable BCC-1- and SCC-25 cells, as shown by a metabolic MTS assays ( Figure 1 ). These observations are in line with data from Steg and colleagues [ 33 ] and Wu et al [ 34 ], reporting similar results after SMO inhibition with cyclopamine in human pancreatic cancer cells, or with vismodegib in colon cancer cells, respectively. In the present study, addition of irradiation only slightly decreased the cellular viability ( Figure 3 ), indicating a non-synergistic effect of combined modality treatment at early times.…”

“…Cyclopamine also failed to induce significant apoptosis in human pancreatic carcinoma cells [ 41 ]. By contrast, colorectal cancer cells exhibited an increased apoptotic fraction when treated with 50 µM vismodegib [ 34 ], suggesting that a cell line-dependent Hh/GLI canonical and/or non-canonical signaling is responsible for induction of apoptotic cell death.…”

Colon cancer stem cells: Potential target for the treatment of colorectal cancer

“…The potency of GDC-0449 was demonstrated on Caco-2 and HT-29 cell lines by its downregulation of GLI1, inhibition of the HH-GLI pathway, and its anti-CSC effects, which were made evident by its capacity to down regulate the CSC surface markers CD44 and ALDH. 65,66 Compelling evidence suggests that the characteristics normally supporting chemoresistance is limited by inhibition of Hh signaling in CSCs that promotes commitment or differentiation and a loss of stemness, as supported by a reduction in clonogenicity and pluripotency markers. In order to prevent tumor relapse and maximize patient outcomes, an attractive approach would be the combinatorial targeting of CSCs and tumor bulk with Hh inhibitors and conventional chemotherapeutic agents and/or radiation.…”

Inhibition of the Sonic Hedgehog Pathway by Cyclopamine or GLI1 siRNA Reduces In Vivo Tumorigenesis of Human Medulloblastoma Cells Xenotransplanted to Immunodeficient Nude Mice

“…Even, it cannot be administered orally, and has several side effects, making it impossible as a candidate to be used in humans [12]. Vismodegib is the first FDA-approved SMO inhibitor [13], in 2012, for the treatment of basal cell carcinoma and has been subsequently studied against colon [14], pancreatic [15], and medulloblasto-ma tumors [16]. In patients suffering from resistance to treatment [17][18][19][20], sonidegib, the second inhibitor of SMO approved by the FDA in 2015 [21], is used [22][23][24].…”