cucurbitacin-i and Lung-Neoplasms

The present study aimed to identify potential anticancer effects of Cucurbitacin I regulators on cell growth of human non‑small cell lung cancer (NSCLC) and to explore their mechanism. The results indicated that the anticancer effects of Cucurbitacin I markedly attenuated cell proliferation, and induced apoptosis in NSCLC. Furthermore, Cucurbitacin I suppressed phosphatidylinositol‑4,5‑bisphosphate 3‑kinase (PI3K), phosphorylation (p)‑AKT and p‑p70S6K pathway in NSCLC. Then, (PI3K) inhibitor increased anticancer effects of Cucurbitacin I on NSCLC. In conclusion, the present results indicated that Cucurbitacin I inhibited cell growth of human NSCLC through PI3K/AKT/p70S6K signaling pathway.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Caspase 3; Caspase 9; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Humans; Lung Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Triterpenes

Natural products are a great source of cancer chemotherapeutic agents. In the present study, the anticancer effects of cucurbitacin I on A549 cells were investigated. Cucurbitacin I decreased cell viability, inhibited colony formation, and induced apoptosis in A549 cells. Cucurbitacin I caused accumulation of autophagosome and dose-dependent expression of LC3II protein. Autophagy inhibitors 3-methyladenine (3-MA) inhibited autophagy induced by cucurbitacin I and relieved cucurbitacin I-triggered cell death and apoptosis in A549 Cells. Cucurbitacin I treatment inhibits the ERK activation and the downstream phosphorylation level of mTOR and STAT3, but not the PI3K/Akt pathway. Furthermore, treatment with the mTOR activator MHY-1485, which also suppressed cucurbitacin I-induced LC3II expression, and also reversed cucurbitacin I-induced cell death and apoptosis. Taken together, these results suggest that cucurbitacin I induced pro-death autophagy through ERK/mTOR/STAT3 signaling cascade in A549 cells.

Topics: A549 Cells; Apoptosis; Autophagy; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Signal Transduction; STAT3 Transcription Factor; TOR Serine-Threonine Kinases; Triterpenes

Signal transducer and activator of transcription 3 (STAT3) signaling reportedly promotes tumor malignancy and recurrence in nonsmall cell lung cancer (NSCLC). It was demonstrated previously that the STAT3 pathway maintains the tumorigenicity and therapeutic resistance of malignant tumors as well as cancer stem cells (CSCs). The objective of the current study was to investigate the effect of the strong STAT3 inhibitor, cucurbitacin I, in prominin-1 (CD133)-positive lung cancer cells.. CD133-positive and CD133-negative NSCLC-derived cells were isolated from 7 patients with NSCLC. CD133-positive NSCLC cells that were treated with or without cucurbitacin I were evaluated for their expression of phosphorylated STAT3 (p-STAT3), tumorigenicity, stemness properties, and resistance to chemotherapeutic drugs and ionizing radiation.. Compared with parental or CD133-negative NSCLC cells, CD133-positive NSCLC cells had greater tumorigenicity, greater radioresistance, and higher expression of octamer-binding transcription factor 4 (Oct-4), Nanog homeobox, and sex-determining region Y, box 2 (Sox2) at high p-STAT3 levels. Cucurbitacin I treatment at 100 nM effectively abrogated STAT3 activation, tumorigenic capacity, sphere formation ability, radioresistance, and chemoresistance in CD133-positive NSCLC cells. Microarray data suggested that cucurbitacin I inhibited the stemness gene signature of CD133-positive NSCLC cells and facilitated the differentiation of CD133-positive NSCLC cells into CD133-negative NSCLC cells. It is noteworthy that 150 nM cucurbitacin I effectively blocked STAT3 signaling and downstream survival targets, such as B-cell chronic lymphocytic leukemia/lymphoma 2 (Bcl-2) and Bcl-2-like 1 (Bcl-xL) expression and induced apoptosis in CD133-positive NSCLC cells. Finally, xenotransplantation experiments revealed that cucurbitacin I plus radiotherapy or chemotherapeutic drugs significantly suppressed tumorigenesis and improved survival in NSCLC-CD133-positive-transplanted, immunocompromised mice.. Targeting STAT3 signaling in CD133-positive NSCLC cells with cucurbitacin I suppressed CSC-like properties and enhanced chemoradiotherapy response. The potential of cucurbitacin I should be verified further in future anti-CSC therapy.

Topics: AC133 Antigen; Aged; Animals; Antigens, CD; Apoptosis; bcl-X Protein; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Cell Separation; Drug Resistance, Neoplasm; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique; Glycoproteins; Homeodomain Proteins; Humans; Lung Neoplasms; Male; Mice; Middle Aged; Nanog Homeobox Protein; Neoplasm Metastasis; Neoplasm Transplantation; Neoplastic Stem Cells; Octamer Transcription Factor-3; Peptides; Proto-Oncogene Proteins c-bcl-2; Radiation Tolerance; Signal Transduction; SOXB1 Transcription Factors; STAT3 Transcription Factor; Triterpenes; Tumor Cells, Cultured