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Wei Sheng, Hongyan Mao, Chuanxi Wang, Ning Yang, Zhe Zhang, Junqing Han
(Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China (mainland))
Med Sci Monit 2018; 24:7850-7861
Natural compounds have been utilized in inhibiting metastasis alone or in combination with other anti-tumor agents. Dehydrocostus lactone (DHC), a natural sesquiterpene lactone, was used to investigate its effect on proliferation of lung cancer cells and on the anti-angiogenic efficacy of doxorubicin.
MATERIAL AND METHODS: Cell proliferation was assessed by MTT assay and clonogenic assay. Apoptosis and migration were assessed by flow cytometry and wound-healing assay, respectively. Western blotting and qPCR were performed for gene and protein expression analysis. Matrigel plug assay was performed for angiogenesis assessment.
RESULTS: Results of the study show that DHC inhibited the survival and proliferation of lung cancer cells (A549 and H460) and enhanced the growth-inhibitory properties of DOX. Cotreatment of DHC enhanced the apoptosis-inducing effects of DOX by activating caspase-9 and caspase-3 followed by cleavage of PARP. Treatment of A549 and H460 cells with DHC caused suppression of HIF-1α, Akt and pAkt, GSK-3β and pGSK-3β, as well as ERK, pERK, mTOR, and p-mTOR. DHC enhanced the effect of DOX by inhibiting migration of A549 cells as observed by wound-healing assay. DHC caused synergistic inhibition of MMP-2 and MMP-9 genes when treated in combination with DOX. DHC further enhanced the anti-angiogenic properties of DOX in mice implanted with Matrigel plugs. DHC suppressed the proliferation of lung cancer cells and enhanced the anti-angiogenic properties of DOX.
CONCLUSIONS: The putative mechanism behind the metastasis-limiting effects of DHC may involve the suppression of Akt/GSK-3β and inhibition of MMP-2 and MMP-9 in lung cancer cells.