Overcoming Temozolomide Resistance in Glioblastoma via Dual Inhibition of NAD+ Biosynthesis and Base Excision Repair

Mar 17, 2011Cancer research

Overcoming glioblastoma resistance to temozolomide by blocking energy production and DNA repair

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Abstract

The combination of BER and NAD(+) biosynthesis inhibition significantly sensitizes glioma cells with elevated MGMT expression and MMR deficiencies.

Glioblastoma multiforme (GBM) has a poor prognosis and low median survival time.
Resistance to the chemotherapy drug temozolomide (TMZ) is common due to high levels of the repair protein MGMT or defects in the mismatch repair pathway.
Inhibition of base excision repair (BER) can enhance the response to TMZ in resistant glioma cells.
Blocking BER leads to the accumulation of DNA repair intermediates that cause cell death through energy depletion.
The efficacy of TMZ may be increased by simultaneously inhibiting BER and the biosynthesis of nicotinamide adenine dinucleotide (NAD(+)).
Targeting both DNA repair and NAD(+) biosynthesis pathways could be an effective strategy for treating resistant and recurrent GBM.

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Glioblastoma multiforme (GBM) is a devastating brain tumor with poor prognosis and low median survival time. Standard treatment includes radiation and chemotherapy with the DNA alkylating agent temozolomide (TMZ). However, a large percentage of tumors are resistant to the cytotoxic effects of the TMZ-induced DNA lesion O(6)-methylguanine due to elevated expression of the repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) or a defect in the mismatch repair (MMR) pathway. Although a majority of the TMZ-induced lesions (N7-methylguanine and N3-methyladenine) are base excision repair (BER) substrates, these DNA lesions are also readily repaired. However, blocking BER can enhance response to TMZ and therefore the BER pathway has emerged as an attractive target for reversing TMZ resistance. Our lab has recently reported that inhibition of BER leads to the accumulation of repair intermediates that induce energy depletion-mediated cell death via hyperactivation of poly(ADP-ribose) polymerase. On the basis of our observation that TMZ-induced cell death via BER inhibition is dependent on the availability of nicotinamide adenine dinucleotide (NAD(+)), we have hypothesized that combined BER and NAD(+) biosynthesis inhibition will increase TMZ efficacy in glioblastoma cell lines greater than BER inhibition alone. Importantly, we find that the combination of BER and NAD(+) biosynthesis inhibition significantly sensitizes glioma cells with elevated expression of MGMT and those deficient in MMR, two genotypes normally associated with TMZ resistance. Dual targeting of these two interacting pathways (DNA repair and NAD(+) biosynthesis) may prove to be an effective treatment combination for patients with resistant and recurrent GBM.

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Overcoming Temozolomide Resistance in Glioblastoma via Dual Inhibition of NAD+ Biosynthesis and Base Excision Repair

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