Abstract
The scaffold of 4-quinolylhydrazone was attached to dihydroartemisinin by the combination and bioisosterism principles to get a dihydroartemisinin derivative called L-A03. The previous study demonstrated that L-A03 inhibited cysteine protease falcipain-2 of Plasmodium falciparum. Our preliminary assay showed that this compound exhibited significant antitumor activity in some cancer cell lines. Besides, cytotoxicity was low against human peripheral blood mononuclear cells. These suggest that L-A03 could be used as a potent antitumor drug. This study indicated that L-A03 induced both apoptosis and autophagy in human breast cancer MCF-7 cells. L-A03 caused autophagy prior to the onset of apoptotic cell death. In the presence of chloroquine, an autophagic inhibitor, L-A03-induced apoptosis was attenuated, indicating that autophagy was indispensable for apoptosis induction. Nitric oxide generation blocked apoptotic cell death, but did not affect autophagy, suggesting that autophagy may take place in the upstream of nitric oxide generation. Moreover, autophagy decreased the generation of nitric oxide. This study provided a new insight on the mechanism of anti-tumor effect of L-A03.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Barsoum MJ, Yuan H, Gerencser AA, Liot G, Kushnareva Y, Graber S, Kovacs I, Lee WD, Waggoner J, Cui J, White AD, Bossy B, Martinou JC, Youle RJ, Lipton SA, Ellisman MH, Perkins GA, Bossy-Wetzel E (2006) Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons. EMBO J 25:3900–3911
Burz C, Berindan-Neagoe I, Balacescu O, Irimie A (2009) Apoptosis in cancer: key molecular signaling pathways and therapy targets. Acta Oncol 48:811–821
Chen HH, Zhou HJ, Wang WQ, Wu GD (2004) Antimalarial dihydroartemisinin also inhibits angiogenesis. Cancer Chemother Pharmacol 53:423–432
Eisenberg-Lerner A, Bialik S, Simon HU, Kimchi A (2009) Life and death partners: apoptosis, autophagy and the cross-talk between them. Cell Death Differ 16:966–975
Fan S, Yu Y, Qi M, Sun Z, Li L, Yao G, Tashiro S, Onodera S, Ikejima T (2012) P53-mediated GSH depletion enhanced the cytotoxicity of NO in silibinin-treated human cervical carcinoma HeLa cells. Free Radic Res 46:1082–1092
Finkel T, Serrano M, Blasco MA (2007) The common biology of cancer and ageing. Nature 448:767–774
Gabriels M, Plaizier-Vercammen J (2004) Design of a dissolution system for the evaluation of the release rate characteristics of artemether and dihydroartemisinin from tablets. Int J Pharm 274:245–260
He H, Feng YS, Zang LH, Liu WW, Ding LQ, Chen LX, Kang N, Hayashi T, Tashiro S, Onodera S, Qiu F, Ikejima T (2014) Nitric oxide induces apoptosis and autophagy; autophagy down-regulates NO synthesis in physalin A-treated A375-S2 human melanoma cells. Food Chem Toxicol 71:128–135
He H, Zang LH, Feng YS, Chen LX, Kang N, Tashiro S, Onodera S, Qiu F, Ikejima T (2013a) Physalin A induces apoptosis via p53-Noxa-mediated ROS generation, and autophagy plays a protective role against apoptosis through p38-NF-kappaB survival pathway in A375-S2 cells. J Ethnopharmacol 148:544–555
He H, Zang LH, Feng YS, Wang J, Liu WW, Chen LX, Kang N, Tashiro S, Onodera S, Qiu F, Ikejima T (2013b) Physalin A induces apoptotic cell death and protective autophagy in HT1080 human fibrosarcoma cells. J Nat Prod 76:880–888
Hwang YP, Yun HJ, Kim HG, Han EH, Lee GW, Jeong HG (2010) Suppression of PMA-induced tumor cell invasion by dihydroartemisinin via inhibition of PKCalpha/Raf/MAPKs and NF-kappaB/AP-1-dependent mechanisms. Biochem Pharmacol 79:1714–1726
Janicke RU, Sprengart ML, Wati MR, Porter AG (1998) Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J Biol Chem 273:9357–9360
Janssen YM, Matalon S, Mossman BT (1997) Differential induction of c-fos, c-jun, and apoptosis in lung epithelial cells exposed to ROS or RNS. Am J Physiol 273:L789–796
Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun MJ (2005) Cancer statistics, 2005. CA Cancer J Clin 55:10–30
Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N (2004) The role of autophagy during the early neonatal starvation period. Nature 432:1032–1036
Luo W, Lu W, Cui K, Liu Y, Wang J, Guo C (2012) N1-{4-[(10S)-Dihydroartemisinin-10-oxyl]}phenylmethylene-N2-(2-methylquinoline-4-yl)hydrazine derivatives as antiplasmodial falcipain-2 inhibitors. Med Chem Res 21:2073–3079
Meijer AJ, Codogno P (2006) Signalling and autophagy regulation in health, aging and disease. Mol Aspects Med 27:411–425
Okada H, Mak TW (2004) Pathways of apoptotic and non-apoptotic death in tumour cells. Nat Rev Cancer 4:592–603
Sarkar S, Korolchuk VI, Renna M, Imarisio S, Fleming A, Williams A, Garcia-Arencibia M, Rose C, Luo S, Underwood BR, Kroemer G, O’Kane CJ, Rubinsztein DC (2011) Complex inhibitory effects of nitric oxide on autophagy. Mol Cell 43:19–32
Savill J, Fadok V (2000) Corpse clearance defines the meaning of cell death. Nature 407:784–788
Swanlund JM, Kregel KC, Oberley TD (2008) Autophagy following heat stress: the role of aging and protein nitration. Autophagy 4:936–939
Tsujimoto Y (1998) Role of Bcl-2 family proteins in apoptosis: apoptosomes or mitochondria? Genes Cells 3:697–707
Wang HJ, Wei XF, Jiang YY, Huang H, Yang Y, Fan SM, Zang LH, Tashiro S, Onodera S, Ikejima T (2010) Silibinin induces the generation of nitric oxide in human breast cancer MCF-7 cells. Free Radic Res 44:577–584
Zang L, He H, Ye Y, Liu W, Fan S, Tashiro S, Onodera S, Ikejima T (2012) Nitric oxide augments oridonin-induced efferocytosis by human histocytic lymphoma U937 cells via autophagy and the NF-kappaB-COX-2-IL-1beta pathway. Free Radic Res 46:1207–1219
Zhong H, Zhao X, Zuo Z, Sun J, Yao Y, Wang T, Liu D, Zhao L (2016) Combating P-glycoprotein-mediated multidrug resistance with 10-O-phenyl dihydroartemisinin ethers in MCF-7 cells. Eur J Med Chem 108:720–729
Acknowledgments
This work was supported by the National Natural Science Foundation of China (No. 81573292) and the National Fund for Talent Training in Basic Science (NO. J1103606)
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no competing interests.
Additional information
Guodong Yao and Hao Chen contributed equally to this work.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Yao, G., Chen, H., Chen, L. et al. Autophagy promotes apoptosis induction through repressed nitric oxide generation in the treatment of human breast cancer MCF-7 cells with L-A03, a dihydroartemisinin derivative. Med Chem Res 26, 1427–1436 (2017). https://doi.org/10.1007/s00044-017-1868-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00044-017-1868-z