PP2A inhibition with LB100 enhances cisplatin cytotoxicity and overcomes cisplatin resistance in medulloblastoma cells

Oncotarget
Winson S HoJohn D Heiss

Abstract

The protein phosphatase 2A (PP2A) inhibitor, LB100, has been shown in pre-clinical studies to be an effective chemo- and radio-sensitizer for treatment of various cancers. We investigated effects associated with LB100 treatment alone and in combination with cisplatin for medulloblastoma (MB) in vitro and in vivo in an intracranial xenograft model. We demonstrated that LB100 had a potent effect on MB cells. By itself, LB100 inhibited proliferation and induced significant apoptosis in a range of pediatric MB cell lines. It also attenuated MB cell migration, a pre-requirement for invasion. When used in combination, LB100 enhanced cisplatin-mediated cytotoxic effects. Cell viability in the presence of 1 uM cisplatin alone was 61% (DAOY), 100% (D341), and 58% (D283), but decreased with the addition of 2 μM of LB100 to 26% (DAOY), 67% (D341), and 27% (D283), (p < 0.005). LB100 suppressed phosphorylation of the STAT3 protein and several STAT3 downstream targets. Also, LB100 directly increased cisplatin uptake and overcame cisplatin-resistance in vitro. Finally, LB100 exhibited potent in vivo anti-neoplastic activity in combination with cisplatin in an intracranial xenograft model.

References

Sep 15, 1999·Proceedings of the National Academy of Sciences of the United States of America·A WoetmannN Odum
Mar 25, 2005·Molecular and Cellular Biochemistry·Shinya MitsuhashiKunimi Kikuchi
Jul 13, 2005·Neuropathology and Applied Neurobiology·J PizemM Popovic
Jul 17, 2007·Cell·Marc Mumby
Nov 4, 2008·Cancer Treatment Reviews·Piero FossatiRoberto Orecchia
Jul 1, 2009·Proceedings of the National Academy of Sciences of the United States of America·Jie LuZhengping Zhuang
Jan 18, 2012·Child's Nervous System : ChNS : Official Journal of the International Society for Pediatric Neurosurgery·Charn-Jung ChangKai-Hsi Lu
Jul 27, 2012·Nature·Paul A NorthcottMichael D Taylor
May 4, 2013·The Lancet Oncology·Danilo Perrotti, Paolo Neviani
Jun 20, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Dongping WeiMeredith A Morgan
Aug 3, 2014·Journal of Experimental & Clinical Cancer Research : CR·Samantha Kaufhold, Benjamin Bonavida
Oct 25, 2014·Nature Reviews. Cancer·Hua YuRichard Jove
Apr 22, 2015·Cancer Biology & Therapy·Christopher S HongZhengping Zhuang
May 16, 2015·Seminars in Pediatric Neurology·Ayman SamkariRoger J Packer
Aug 25, 2015·BMJ Case Reports·John Ross Crawford, Michael L Levy

❮ Previous
Next ❯

Citations

Aug 24, 2018·Frontiers in Oncology·Z Ping LinElena S Ratner
Aug 28, 2020·Hereditas·Xiao LeiBaolin Qu
Apr 29, 2020·Journal of Neuro-oncology·Dominic MaggioZhengping Zhuang
Jan 1, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Vincent ChungJohn S Kovach
Nov 7, 2017·The International Journal of Biochemistry & Cell Biology·Caitlin M O'ConnorGoutham Narla
Jul 3, 2021·Cancers·Jean-Paul BryantYeshavanth Kumar Banasavadi-Siddegowda
Jul 14, 2021·Molecular Cancer Therapeutics·Tamara MirzapoiazovaRavi Salgia

❮ Previous
Next ❯

Methods Mentioned

BETA
surgical resection
xenograft
phosphatase assay
flow cytometry
xenografts
Assay
protein assay
FACS

Software Mentioned

Image Studio
NIS
Kaluza
Summit
living image
Elements Imaging

Related Concepts

Related Feeds

Cell Migration in Cancer and Metastasis

Migration of cancer cells into surrounding tissue and the vasculature is an initial step in tumor metastasis. Discover the latest research on cell migration in cancer and metastasis here.

Apoptosis in Cancer

Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.

Cell Migration

Cell migration is involved in a variety of physiological and pathological processes such as embryonic development, cancer metastasis, blood vessel formation and remoulding, tissue regeneration, immune surveillance and inflammation. Here is the latest research.

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis