cephalomannine and Lung-Neoplasms

Lung cancer (LC) is one of the leading causes of cancer-related death. As one of the key features of tumor microenvironment, hypoxia conditions are associated with poor prognosis in LC patients. Upregulation of hypoxic-induced factor-1α (HIF-1α) leads to the activation of various factors that contribute to the increased drug resistance, proliferation, and migration of tumor cells. Apurinic/apyrimidinic endonuclease-1 (APEX1) is a multi-functional protein that regulates several transcription factors, including HIF-1α, that contribute to tumor growth, oxidative stress responses, and DNA damage. In this study, we explored the mechanisms underlying cell responses to hypoxia and modulation of APEX1, which regulate HIF-1α and downstream pathways. We found that hypoxia-induced APEX1/HIF-1α pathways regulate several key cellular functions, including reactive oxygen species (ROS) production, carbonic anhydrase 9 (CA9)-mediated intracellular pH, migration, and angiogenesis. Cephalomannine (CPM), a natural compound, exerted inhibitory effects in hypoxic LC cells via the inhibition of APEX1/HIF-1α interaction in vitro and in vivo. CPM can significantly inhibit cell viability, ROS production, intracellular pH, and migration in hypoxic LC cells as well as angiogenesis of HUVECs under hypoxia through the inhibition of APEX1/HIF-1α interaction. Taken together, CPM could be considered as a promising compound for LC treatment.

Topics: Animals; DNA-(Apurinic or Apyrimidinic Site) Lyase; Humans; Lung Neoplasms; Mice; Mice, Nude; Reactive Oxygen Species; Taxoids; Tumor Microenvironment

Lx2-32c, a novel taxane derivative, is a semisynthetic analogue from cephalomannine. Its antitumor activity in vivo and in vitro was investigated in this study. Lx2-32c was cytotoxic (IC50=1.7+/-1.6nM) to various human tumor cell lines after 72h incubation. In vitro it enhanced the rate of tubulin polymerization in a dose-dependent manner and induced the bundling of microtubule in BGC-823 cells with the mode similar to that of paclitaxel. As determined by flow cytometry, after either 12 or 24h exposure, Lx2-32c caused BGC-823 cells G2/M phase arrest in a time- and dose-dependent manner. Moreover, we demonstrated that Lx2-32c had significant antitumor activity on BGC-823 (human gastric carcinoma) and A549 (human non-small cell lung carcinoma) xenograft in nude mice. These data suggest that Lx2-32c is a microtubule-stabilizing agent, which has significant antitumor activity in vitro and in vivo.

Topics: Animals; Antineoplastic Agents, Phytogenic; Bridged-Ring Compounds; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Humans; Lung Neoplasms; Mice; Mice, Nude; Microtubules; Paclitaxel; Stomach Neoplasms; Taxoids; Tubulin; Xenograft Model Antitumor Assays