Some potent
chemotherapy drugs including
tubulin-binding agents had been developed from nature plants, such as
podophyllotoxin and
paclitaxel. However, poor cytotoxic selectivity, serious side-effects, and limited effectiveness are still the major concerns in their therapeutic application. We developed a fully synthetic
podophyllotoxin derivative named Ching001 and investigated its anti-
tumor growth effects and mechanisms in
lung cancer preclinical models. Ching001 showed a selective cytotoxicity to different
lung cancer cell lines but not to normal lung cells. Ching001 inhibited the polymerization of microtubule resulting in mitotic arrest as evident by the accumulation of mitosis-related
proteins,
survivin and aurora B, thereby leading to DNA damage and apoptosis. Ching001 also activated pro-apoptotic ER stress signaling pathway.
Intraperitoneal injection of 2 mg/kg Ching001 significantly inhibited the
tumor growth of A549 xenograft, while injection of 0.2 mg/kg Ching001 decreased the lung colonization ability of A549 cells in experimental
metastasis assay. These anti-
tumor growth and lung colonization inhibition effects were stronger than those of
paclitaxel treatment at the same dosage. The xenograft
tumor tissue stains further confirmed that Ching001 induced mitosis arrest and
tumor apoptosis. In addition, the hematology and biochemistry tests of blood samples as well as tissue examinations indicated that Ching001 treatment did not show apparent organ toxicities in tested animals. We provided preclinical evidence that novel synthetic microtubule inhibitor Ching001, which can trigger DNA damage and apoptosis by inducing mitotic arrest and ER stress, is a potential anti-
cancer compound for further drug development.