Medium Throughput Biochemical Compound Screening Identifies Novel Agents for Pharmacotherapy of Neurofibromatosis Type 1

Overview

Journal Biochimie

Specialty Biochemistry

Date 2017 Jan 10

PMID 28065690

Citations 8

Authors

Galina Semenova

Dina S Stepanova

Sergey M Deyev

Jonathan Chernoff

Affiliations

Soon will be listed here.

Abstract

The variable manifestation of phenotypes that occur in patients with neurofibromatosis type 1 (NF1) includes benign and malignant neurocutaneous tumors for which no adequate treatment exists. Cell-based screening of known bioactive compounds library identified the protein phosphatase 2A (PP2A) inhibitor Cantharidin and the L-type calcium channel blocker Nifedipine as potential candidates for NF1 pharmacotherapy. Validation of screening results using human NF1-associated malignant peripheral nerve sheath tumor (MPNST) cells showed that Cantharidin effectively impeded MPNST cell growth, while Nifedipine treatment significantly decreased local tumor growth in an MPNST xenograft animal model. These data suggest that inhibitors of PP2A, as well as calcium channel blockers, might be used in broader MPNST preclinical studies as single agents or in combinatorial therapeutic strategies.

Citing Articles

Pharmacogenomic synthetic lethal screens reveal hidden vulnerabilities and new therapeutic approaches for treatment of NF1-associated tumors.

Williams K, Larsson A, Keller B, Chaney K, Williams R, Bhunia M bioRxiv. 2024; .

PMID: 38585724 PMC: 10996510. DOI: 10.1101/2024.03.25.585959.

A review for cell-based screening methods in drug discovery.

Wei F, Wang S, Gou X Biophys Rep. 2023; 7(6):504-516.

PMID: 37288368 PMC: 10210057. DOI: 10.52601/bpr.2021.210042.

Malignant peripheral nerve sheath tumor: models, biology, and translation.

Somatilaka B, Sadek A, McKay R, Le L Oncogene. 2022; 41(17):2405-2421.

PMID: 35393544 PMC: 9035132. DOI: 10.1038/s41388-022-02290-1.

Neurofibromin and suppression of tumorigenesis: beyond the GAP.

Mo J, Moye S, McKay R, Le L Oncogene. 2022; 41(9):1235-1251.

PMID: 35066574 PMC: 9063229. DOI: 10.1038/s41388-021-02156-y.

Familial left cervical neurofibromatosis 1 with scoliosis: A case report.

Mu X, Zhang H, Shen Y, Yang H World J Clin Cases. 2021; 9(29):8839-8845.

PMID: 34734064 PMC: 8546810. DOI: 10.12998/wjcc.v9.i29.8839.

References

Taylor J, Simpson R . Inhibition of cancer cell growth by calcium channel antagonists in the athymic mouse. Cancer Res. 1992; 52(9):2413-8. View

Johannessen C, Reczek E, James M, Brems H, Legius E, Cichowski K . The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc Natl Acad Sci U S A. 2005; 102(24):8573-8. PMC: 1142482. DOI: 10.1073/pnas.0503224102. View

Trovo-Marqui A, Tajara E . Neurofibromin: a general outlook. Clin Genet. 2006; 70(1):1-13. DOI: 10.1111/j.1399-0004.2006.00639.x. View

Tonsgard J . Clinical manifestations and management of neurofibromatosis type 1. Semin Pediatr Neurol. 2006; 13(1):2-7. DOI: 10.1016/j.spen.2006.01.005. View

Zhu Y, Guignard F, Zhao D, Liu L, Burns D, Mason R . Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell. 2005; 8(2):119-30. PMC: 3024718. DOI: 10.1016/j.ccr.2005.07.004. View

Loughlin K . Calcium channel blockers and prostate cancer. Urol Oncol. 2014; 32(5):537-8. DOI: 10.1016/j.urolonc.2013.08.001. View

Lakkis M, Tennekoon G . Neurofibromatosis type 1. I. General overview. J Neurosci Res. 2000; 62(6):755-63. DOI: 10.1002/1097-4547(20001215)62:6<755::AID-JNR1>3.0.CO;2-W. View

Capiod T . Cell proliferation, calcium influx and calcium channels. Biochimie. 2011; 93(12):2075-9. DOI: 10.1016/j.biochi.2011.07.015. View

Evans D, Baser M, McGaughran J, Sharif S, Howard E, Moran A . Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. 2002; 39(5):311-4. PMC: 1735122. DOI: 10.1136/jmg.39.5.311. View

10.

Niwa H, Iwase K, Takiguchi M, Mori M, Abe S, Abe K . Endoderm-specific gene expression in embryonic stem cells differentiated to embryoid bodies. Exp Cell Res. 1996; 229(1):27-34. DOI: 10.1006/excr.1996.0340. View

11.

Wang G . Medical uses of mylabris in ancient China and recent studies. J Ethnopharmacol. 1989; 26(2):147-62. DOI: 10.1016/0378-8741(89)90062-7. View

12.

Ferner R . Neurofibromatosis 1. Eur J Hum Genet. 2006; 15(2):131-8. DOI: 10.1038/sj.ejhg.5201676. View

13.

Carroll S . The Challenge of Cancer Genomics in Rare Nervous System Neoplasms: Malignant Peripheral Nerve Sheath Tumors as a Paradigm for Cross-Species Comparative Oncogenomics. Am J Pathol. 2016; 186(3):464-77. PMC: 4816695. DOI: 10.1016/j.ajpath.2015.10.023. View

14.

Shen M, Wu M, Chen L, Zhi Q, Gong F, Chen K . Cantharidin represses invasion of pancreatic cancer cells through accelerated degradation of MMP2 mRNA. Sci Rep. 2015; 5:11836. PMC: 4488834. DOI: 10.1038/srep11836. View

15.

Ratner N, Miller S . A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor. Nat Rev Cancer. 2015; 15(5):290-301. PMC: 4822336. DOI: 10.1038/nrc3911. View

16.

Rad E, Tee A . Neurofibromatosis type 1: Fundamental insights into cell signalling and cancer. Semin Cell Dev Biol. 2016; 52:39-46. DOI: 10.1016/j.semcdb.2016.02.007. View

17.

To K, Ho Y, Au-Yeung S . In vitro and in vivo suppression of growth of hepatocellular carcinoma cells by novel traditional Chinese medicine-platinum anti-cancer agents. Anticancer Drugs. 2005; 16(8):825-35. DOI: 10.1097/01.cad.0000175586.31940.50. View

18.

McDermott M, Browne B, Conlon N, OBrien N, Slamon D, Henry M . PP2A inhibition overcomes acquired resistance to HER2 targeted therapy. Mol Cancer. 2014; 13:157. PMC: 4230643. DOI: 10.1186/1476-4598-13-157. View

19.

Sorkin E, Clissold S, Brogden R . Nifedipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy, in ischaemic heart disease, hypertension and related cardiovascular disorders. Drugs. 1985; 30(3):182-274. DOI: 10.2165/00003495-198530030-00002. View

20.

Kiely M, Kiely P . PP2A: The Wolf in Sheep's Clothing?. Cancers (Basel). 2015; 7(2):648-69. PMC: 4491676. DOI: 10.3390/cancers7020648. View