Inhibition of Non-Small Cell Lung Cancer Cells by Oxy210, an Oxysterol-Derivative that Antagonizes TGFβ and Hedgehog Signaling.

Stappenbeck Stappenbeck,Wang Wang,Tang Tang,Parhami Parhami,Zhang Zhang

doi:10.3390/cells8101297

Stappenbeck Stappenbeck, Wang Wang + Show 3 more

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https://doi.org/10.3390/cells8101297

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Abstract

Non-Small Cell Lung Cancer (NSCLC) is a common malignancy and leading cause of death by cancer. Metastasis and drug resistance are serious clinical problems encountered in NSCLC therapy. Aberrant activation of the Transforming Growth Factor beta (TGFβ) and Hedgehog (Hh) signal transduction cascades often associate with poor prognosis and aggressive disease progression in NSCLC, as these signals can drive cell proliferation, angiogenesis, metastasis, immune evasion and emergence of drug resistance. Therefore, simultaneous inhibition of TGFβ and Hh signaling, by a single agent, or in combination with other drugs, could yield therapeutic benefits in NSCLC and other cancers. In the current study, we report on the biological and pharmacological evaluation of Oxy210, an oxysterol-based dual inhibitor of TGFβ and Hh signaling. In NSCLC cells, Oxy210 inhibits proliferation, epithelial-mesenchymal transition (EMT) and invasive activity. Combining Oxy210 with Carboplatin (CP) increases the anti-proliferative response to CP and inhibits TGFβ-induced resistance to CP in A549 NSCLC cells. In addition, Oxy210 displays encouraging drug-like properties, including chemical scalability, metabolic stability and oral bioavailability in mice. Unlike other known inhibitors, Oxy210 antagonizes TGFβ and Hh signaling independently of TGFβ receptor kinase inhibition and downstream of Smoothened, respectively.

Highlights

Non-Small Cell Lung Cancer (NSCLC), which accounts for 85% of all lung cancers, is a common malignancy and leading cause of death by cancer worldwide, implicated in nearly 20% of all cancer mortality [1,2]
CAPAN-1 conditioned medium (CM) that we previously reported to contain Hh ligands [22] and found that Oxy210 robustly inhibited the mRNA expression of ligand-induced Hh target genes Gli1 and Ptch1 (Figure 4a)
Since Gli1 has been reported to be involved in transcription of TGFβ target genes [16] and given the inhibitory effects of Oxy210 on Hh signaling, we sought to examine the possibility that Oxy210 could inhibit TGFβ target gene expression via suppression of Gli signaling

Summary

Introduction

Non-Small Cell Lung Cancer (NSCLC), which accounts for 85% of all lung cancers, is a common malignancy and leading cause of death by cancer worldwide, implicated in nearly 20% of all cancer mortality [1,2]. Despite many available generic treatment options, such as chemotherapy, radiation therapy, surgery and decades of research and clinical experimentation with promising approaches and new cancer drugs, NSCLC continues to be associated with poor prognoses and a lower five-year survival rate than many other forms of cancer [2]. While the five-year survival rate for metastatic lung cancer stands at less than 5%, the outlook for cases diagnosed at an early stage is much improved. Only a minority of NSCLC cases can be diagnosed and treated while the tumor is still localized within the lungs. Metastasis and drug resistance are known to be major causes of failure in NSCLC therapy. Metastases occur frequently in NSCLC, locally into lymph nodes and the thoracic wall as well as into distant tissues, such as the brain, bones and the adrenal glands [3].

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