The strategy for enhancing temozolomide against malignant glioma

Abstract

A combined therapy of the alkylating agent temozolomide (TMZ) and radiotherapy is standard treatment, and it improves the survival of patients with newly diagnosed glioblastoma (GBM). The DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) removes the most cytotoxic lesions generated by TMZ, O(6)-methylguanine, establishing MGMT as one of the most important DNA repair mechanisms of TMZ-induced DNA damage. Thus, the expression of MGMT, its activity, and its promoter methylation status are associated with the response of GBM to TMZ, confirming that MGMT promotes clinical resistance to TMZ. Previous studies have shown that a variety of drugs such as interferon-β (IFN-β), levetiracetam (LEV), resveratrol, and valproic acid (VAP) increased the sensitivity of TMZ through MGMT-dependent or MGMT-independent mechanisms. In this review, we describe drugs and promising molecules that influence the responsiveness of GBM to TMZ and discuss their putative mechanism of action. In MGMT-positive GBMs, drugs that modulate MGMT activity could enhance the therapeutic activity of TMZ. Thus, administration of these drugs as an adjunct to TMZ chemotherapy may have clinical applications in patients with malignant gliomas to improve the outcome.

Keywords: MGMT; chemosensitivity; glioma; interferon-β; levetiracetam; resveratrol; temozolomide; valproic acid.

Figure 1

Levetiracetam increases HDAC1 transcription and recruit HDAC1/mSin3A corepressor, which binds MGMT promoter region intermediated by p53. This complex of three components inhibits MGMT transcription.

Figure 2

Two pathways of methylated DNA repair. TMZ generates a spectrum of DNA lesions including O⁶-methylguanine, N³-methyladenine, and N⁷-methylguanine. MGMT eliminates directly the methyl group from O⁶-methylguanine, whereas BER pathway includes multistep reaction by DNA glycosylase (APNG or MPG), endonuclease, polymerase, and DNA ligase. DNA glycosylase recognizes and removes the damaged bases. The abasic site is then hydrolyzed by endonuclease, resulting in the incision of the damaged DNA strand. Polymerase inserts a single nucleotide and DNA ligase completes the repair process. PARP, one of the polymerases of BER, catalyzes the transfer of ADP-ribose units from NAD⁺ to target proteins including PARP itself. Therefore, inhibition or hyperactivation of PARP leads to accumulation of broken DNA or NAD⁺ depletion respectively, consequently inducing cell death.