Reference Detail

Ref Type

Journal Article

PMID

(25376608)

Authors

Chang KE, Wei BR, Madigan JP, Hall MD, Simpson RM, Zhuang Z, Gottesman MM

Title

The protein phosphatase 2A inhibitor LB100 sensitizes ovarian carcinoma cells to cisplatin-mediated cytotoxicity.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	14	1	2015 Jan	90-100	Mol Cancer Ther

URL

Abstract Text

Despite early positive response to platinum-based chemotherapy, the majority of ovarian carcinomas develop resistance and progress to fatal disease. Protein phosphatase 2A (PP2A) is a ubiquitous phosphatase involved in the regulation of DNA-damage response (DDR) and cell-cycle checkpoint pathways. Recent studies have shown that LB100, a small-molecule inhibitor of PP2A, sensitizes cancer cells to radiation-mediated DNA damage. We hypothesized that LB100 could sensitize ovarian cancer cells to cisplatin treatment. We performed in vitro studies in SKOV-3, OVCAR-8, and PEO1, -4, and -6 ovarian cancer lines to assess cytotoxicity potentiation, cell-death mechanism(s), cell-cycle regulation, and DDR signaling. In vivo studies were conducted in an intraperitoneal metastatic mouse model using SKOV-3/f-Luc cells. LB100 sensitized ovarian carcinoma lines to cisplatin-mediated cell death. Sensitization via LB100 was mediated by abrogation of cell-cycle arrest induced by cisplatin. Loss of the cisplatin-induced checkpoint correlated with decreased Wee1 expression, increased cdc2 activation, and increased mitotic entry (p-histone H3). LB100 also induced constitutive hyperphosphorylation of DDR proteins (BRCA1, Chk2, and γH2AX), altered the chronology and persistence of JNK activation, and modulated the expression of 14-3-3 binding sites. In vivo, cisplatin sensitization via LB100 significantly enhanced tumor growth inhibition and prevented disease progression after treatment cessation. Our results suggest that LB100 sensitizes ovarian cancer cells to cisplatin in vitro and in vivo by modulation of the DDR pathway and cell-cycle checkpoint abrogation.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
LB-100	LB-100	0	2

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
LB-100		LB100\|LB 100	PP2A Inhibitor 2	LB-100 is a small molecule that inhibits PP2A activity, resulting in increased sensitivity of tumor cells to DNA damaging agents, including chemotherapy and radiotherapy (PMID: 25376608, PMID: 31935881, PMID: 30679389, PMID: 32342332).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TP53 inact mut	ovarian cancer	sensitive	Cisplatin + LB-100	Preclinical	Actionable	In a preclinical study, LB100 treatment decreased PP2A activity and increased sensitivity to Platinol (cisplatin) in a cisplatin-resistant ovarian cancer cell line harboring a TP53 inactivating mutation in culture (PMID: 25376608).	25376608
TP53 loss	ovarian cancer	sensitive	Cisplatin + LB-100	Preclinical	Actionable	In a preclinical study, LB100 treatment decreased PP2A activity and increased sensitivity to Platinol (cisplatin) in cisplatin-resistant ovarian cancer cells with TP53 loss in culture and in xenograft models (PMID: 25376608).	25376608