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β-Lapachone Enhances Mre11-Rad50-Nbs1 Complex Expression in Cisplatin-Induced Nephrotoxicity

β-Lapachone Enhances Mre11-Rad50-Nbs1 Complex Expression in Cisplatin-Induced Nephrotoxicity

Tae-Won Kim, Young-Jung Kim, Hyun-Tae Kim, Se-Ra Park, Ju-Young Jung

Pharmacol Rep. 2016 Feb;68(1):27-31.

PMID: 26721347

Abstract:

Background:
Recent studies suggest a potential involvement of the Mre11-Rad50-Nbs1 (MRN) complex, a DNA double-strand breaks (DSBs) sensor, in the development of nephrotoxicity following cisplatin administration. β-Lapachone is a topoisomerase I inhibitor known to reduce cisplatin-induced nephrotoxicity. In this study, by assessing MRN complex expression, we explored whether β-lapachone was involved in DNA damage response in the context of cisplatin-induced nephrotoxicity.
Methods:
Male Balb/c mice were randomly allocated to 4 groups: control, β-lapachone alone, cisplatin alone, and β-lapachone+cisplatin. β-Lapachone was administered with the diet (0.066%) for 2 weeks prior to cisplatin injection (18mg/kg). All mice were sacrificed 3 days after cisplatin treatment.
Results:
In the cisplatin-alone group, renal function was disrupted and MRN complex expression increased. As expected, β-lapachone co-treatment attenuated cisplatin-induced pathologic alterations. Notably, although β-lapachone markedly decreased cisplatin-induced renal cell apoptosis and DSBs formation, the β-lapachone+cisplatin group showed the highest MRN complex expression. Moreover, β-lapachone treatment increased the basal expression level of the MRN complex, which was accompanied by enhanced basal expression of SIRTuin1, which is known to regulate Nbs1 acetylation.
Conclusion:
Although, it remains unclear how β-lapachone induces MRN complex expression, our findings suggest that β-lapachone might affect MRN complex expression and participate in DNA damage recovery in cisplatin-induced nephrotoxicity.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP4707328	β-Lapachone		4707-32-8	Price

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