Cell lines

Canine kidney MDCKII cell lines

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.

Reaction Conditions

8h; 5 μM

Applications

In the MDCKII parental cell line, which overexpressed human (h) ABCB1, both apically and basolaterally directed translocation of rucaparib were the same. Treatment of the cells with the ABCB1 inhibitor zosuquidar resulted in a slight decrease in apically directed transport, which could be either due to a specific inhibition of an unidentified rucaparib uptake transporter at the basolateral side, or inhibition of endogenous canine ABCB1. The result shown that rucaparib is a transported substrate of ABCB1.

Animal models

female WT, Abcb1a/1b mice of a >99% FVB genetic background

Dosage form

10 mg/kg; oral taken

Applications

We analyzed the separate and combined effect of Abcg2 and Abcb1a/1b activity on the in vivo disposition of orally administered rucaparib at a dose of 10 mg/kg in wild-type (WT) and single and combination Abcg2 and Abcb1a/1b knockout mice. In vivo, oral availability (plasma AUC0-1 and AUC0-24) and brain levels of rucaparib at 1 and 24 h were increased by the absence of both Abcg2 and Abcb1a/1b after oral administration of rucaparib at 10 mg/kg.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

Rucaparib, also named as AG-014699 or PF-01367338, is a poly (ADP ribose) polymerase (PARP) inhibitor. PARP is a DNA damage-activated nuclear enzyme that has a key signaling role in the base excision repair pathway. So, rucaparib has been also found to be most effective in cells deficient in DNA repair, where the cells deficient are caused by exposure to genotoxic agents, such as irradiation produces DNA damage and its toxicity is augmented when the DNA repair is impaired. Increased radiosensitivity in presence of rucaparib was associated with persistent DNA breaks as determined by gamma-H2AX and p53BP1 foci. Rucaparib radiosensitizes prostate cancer cells, most effectively those that are PTEN-deficient and are expressing ETS gene fusion proteins, which inhibits NHEJ DNA repair.

References

[1].Ruth Plummer, Paul Lorigan, Neil Steven, Lucy Scott, Mark R. Middleton, Richard H. Wilson, Evan Mulligan, Nicola Curtin, Diane Wang, Raz Dewji, Antonello Abbattista, Jorge Gallo, Hilary Calvert. A phase II study of the potent PARP inhibitor, Rucaparib (PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation.
[2].Payel Chatterjee, Gaurav Choudhary, Warren D. Heston, Eric A. Klein, Alex Almasan. The PARP inhibitor rucaparib radiosensitizes prostate cancer cells, most effectively those that are PTEN-deficient and are expressing ETS gene fusion proteins, which inhibit NHEJ DNA repair. Cancer Research. 2012. 72: B27.