glaucocalyxin-a and Lung-Neoplasms

Lung cancer is one of the fastest growing malignancies in morbidity and mortality, and current therapies are in general not sufficiently effective for this deadly disease. This study characterizes the anticancer effects of glaucocalyxin A (GLA) and explores the underlying mechanisms using human non-small cell lung carcinoma (NSCLC) cells. First, our data showed that GLA suppressed the viability of cancer cells, whereas no effect was observed in the normal bronchial epithelial cell BEAS-2B cells. Second, GLA inhibited colony formation, induced apoptosis of cancer cells. Third, GLA downregulated the expression of B-cell lymphoma-2 (Bcl-2) protein; upregulated the expression of Bcl2-associated X protein (Bax), and strengthened cleavage of caspase 3 and polyadenyl diphosphate ribose polymerase (PARP). Fourth, GLA also diminished mitochondrial membrane potential and inhibited phosphatidylinositol 3-kinase (PI3K)/Akt/ glycogen synthase kinase-3β (GSK3β) pathway. In addition, injection of GLA (20 mg/kg) every 2 days significantly inhibited A549 xenograft tumour growth, accompanied by increased apoptosis and decreased proliferation. Together, our study provides evidence that the anticancer effect of GLA in NSCLC is mediated by inducing apoptosis through inhibiting PI3K/Akt/GSK3β pathway and suggests that GLA may be used as a promising natural medicine for NSCLC therapy.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Diterpenes, Kaurane; Glycogen Synthase Kinase 3 beta; Humans; Lung Neoplasms; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Signal Transduction

Metastatic osteosarcoma usually has an unsatisfactory response to the current standard chemotherapy and causes poor prognosis. Currently, epithelial-mesenchymal transition (EMT) is reported as a critical event in osteosarcoma metastasis. Glaucocalyxin A, a bioactive ent-kauranoid diterpenoid, exerts anti-cancer effect on osteosarcoma by inducing apoptosis in previous study. However, the effect of Glaucocalyxin A on EMT and metastasis of osteosarcoma is unclear. In this study, we investigated the potential mechanisms of Glaucocalyxin A on EMT and metastasis of osteosarcoma. We found that Glaucocalyxin A inhibited migration and invasion of MG-63 and 143B cells. Moreover, Glaucocalyxin A increased the protein and mRNA levels of E-cadherin and decreased the protein and transcription expression of N-cadherin, Vimentin. Glaucocalyxin A also inhibited the protein and mRNA levels of EMT-associated transcription factor including Snail and Slug. Furthermore, Glaucocalyxin A inhibited transforming growth factor-β1 (TGF-β1)-induced migration, invasion and EMT of low-metastatic osteosarcoma U2OS cells. Glaucocalyxin A inhibited TGF-β-induced phosphorylation of Smad 2/3 in osteosarcoma U2OS cells. Finally, we established transplanted metastatic models of highly metastatic osteosarcoma 143B cells. Glaucocalyxin A inhibited lung metastasis in vivo. Interestingly, Glaucocalyxin A increased the protein expression of E-cadherin and reduced the protein expression of N-cadherin and Vimentin. Glaucocalyxin A inhibited the protein expression of Snail and Slug in vivo. In summary, this study demonstrated that Glaucocalyxin A inhibited EMT and TGF-β1-induced EMT by inhibiting TGF-β1/Smad2/3 signaling pathway in osteosarcoma. Therefore, Glaucocalyxin A might be a promising candidate against the metastasis of human osteosarcoma.

Topics: Animals; Bone Neoplasms; Cadherins; Cell Line, Tumor; Cell Movement; Diterpenes, Kaurane; Epithelial-Mesenchymal Transition; Humans; Lung Neoplasms; Mice; Mice, Nude; Osteosarcoma; Phosphorylation; Signal Transduction; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta1; Vimentin