TY - JOUR
T1 - Targeted NF1 cancer therapeutics with multiple modes of action
T2 - small molecule hormone-like agents resembling the natural anticancer metabolite, 2-methoxyoestradiol
AU - Shen, Yu Chi
AU - Upadhyayula, Ravi
AU - Cevallos, Stephanie
AU - Messick, Ryan J.
AU - Hsia, Tammy
AU - Leese, Mathew P.
AU - Jewett, Douglas M.
AU - Ferrer-Torres, Daysha
AU - Roth, Therese M.
AU - Dohle, Wolfgang
AU - Potter, Barry V L
AU - Barald, Kate F.
PY - 2015/10/20
Y1 - 2015/10/20
N2 - Background:Both the number and size of tumours in NF1 patients increase in response to the rise in steroid hormones seen at puberty and during pregnancy. The size of tumours decreases after delivery, suggesting that hormone-targeting therapy might provide a viable new NF1 treatment approach. Our earlier studies demonstrated that human NF1 tumour cell lines either went through apoptosis or ceased growth in the presence of 2-methoxyoestradiol (2ME2), a naturally occurring anticancer metabolite of 17-β estradiol. Previous reports of treatment with sulfamoylated steroidal and non-steroidal derivatives of 2ME2 showed promising reductions in tumour burden in hormone-responsive cancers other than NF1. Here we present the first studies indicating that 2ME2 derivatives could also provide an avenue for treating NF1, for which few treatment options are available.Methods:STX3451, (2-(3-Bromo-4,5-dimethoxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline), a non-steroidal sulphamate analogue of 2ME2, was tested in dose-dependent studies of malignant and benign NF1 human tumour cell lines and cell lines with variable controlled neurofibromin expression. The mechanisms of action of STX3451 were also analysed.Results:We found that STX3451-induced apoptosis in human malignant peripheral nerve sheath tumour (MPNST) cell lines, even in the presence of elevated oestrogen and progesterone. It inhibits both PI3 kinase and mTOR signalling pathways. It disrupts actin- and microtubule-based cytoskeletal structures in cell lines derived from human MPNSTs and in cells derived from benign plexiform neurofibromas. STX3451 selectively kills MPNST-derived cells, but also halts growth of other tumour-derived NF1 cell lines.Conclusion:STX3451 provides a new approach for inducing cell death and lowering tumour burden in NF1 and other hormone-responsive cancers with limited treatment options.
AB - Background:Both the number and size of tumours in NF1 patients increase in response to the rise in steroid hormones seen at puberty and during pregnancy. The size of tumours decreases after delivery, suggesting that hormone-targeting therapy might provide a viable new NF1 treatment approach. Our earlier studies demonstrated that human NF1 tumour cell lines either went through apoptosis or ceased growth in the presence of 2-methoxyoestradiol (2ME2), a naturally occurring anticancer metabolite of 17-β estradiol. Previous reports of treatment with sulfamoylated steroidal and non-steroidal derivatives of 2ME2 showed promising reductions in tumour burden in hormone-responsive cancers other than NF1. Here we present the first studies indicating that 2ME2 derivatives could also provide an avenue for treating NF1, for which few treatment options are available.Methods:STX3451, (2-(3-Bromo-4,5-dimethoxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline), a non-steroidal sulphamate analogue of 2ME2, was tested in dose-dependent studies of malignant and benign NF1 human tumour cell lines and cell lines with variable controlled neurofibromin expression. The mechanisms of action of STX3451 were also analysed.Results:We found that STX3451-induced apoptosis in human malignant peripheral nerve sheath tumour (MPNST) cell lines, even in the presence of elevated oestrogen and progesterone. It inhibits both PI3 kinase and mTOR signalling pathways. It disrupts actin- and microtubule-based cytoskeletal structures in cell lines derived from human MPNSTs and in cells derived from benign plexiform neurofibromas. STX3451 selectively kills MPNST-derived cells, but also halts growth of other tumour-derived NF1 cell lines.Conclusion:STX3451 provides a new approach for inducing cell death and lowering tumour burden in NF1 and other hormone-responsive cancers with limited treatment options.
KW - Akt PKB
KW - anticancer drug
KW - apoptosis
KW - mTOR complex (mTORC)
KW - multifaceted tumour therapeutic
KW - Signal transduction pathways, endocrine/oestrogen-related cancers
KW - tubulin-targeted agents
UR - http://www.scopus.com/inward/record.url?scp=84945491534&partnerID=8YFLogxK
UR - http://dx.doi.org/10.1038/bjc.2015.345
U2 - 10.1038/bjc.2015.345
DO - 10.1038/bjc.2015.345
M3 - Article
AN - SCOPUS:84945491534
VL - 113
SP - 1158
EP - 1167
JO - British Journal of Cancer
JF - British Journal of Cancer
SN - 0007-0920
IS - 8
ER -
