Leukemia cells are sensitized to temozolomide, carmustine and melphalan by the inhibition of O6-methylguanine-DNA methyltransferase

Abstract

Abstract. The cytotoxicity of the monofunctional alkylator, temozolomide (TMZ), is known to be mediated by mismatch repair (MMR) triggered by O 6 -alkylguanine. By contrast, the cytotoxicity of bifunctional alkylators, including carmustine (BCNU) and melphalan (MEL), depends on interstrand crosslinks formed through O 6 -alkylguanine, which is repaired by nucleotide excision repair and recombination. O 6 -alkylguanine is removed by O 6 -methylguanine-DNA methyltransferase (MGMT). The aim of the present study was to evaluate the cytotoxicity of TMZ, BCNU and MEL in two different leukemic cell lines (HL-60 and MOLT-4) in the context of DNA repair. The transcript levels of MGMT, ERCC1, hMLH1 and hMSH2 were determined using reverse transcription-quantitative polymerase chain reaction. In addition, the proliferation was measured using the trypan blue exclusion assay. Drug sensitivity was found to vary between the two cell lines. Treatment of the cells with TMZ, BCNU or MEL in combination with O 6 -benzylguanine, an MGMT inhibitor, was demonstrated to sensitize the two cell lines to these agents. However, the extent of sensitization was not found to be correlated with the expression levels of MGMT transcripts. Furthermore, the drug sensitivity was also not associated with the transcript levels of ERCC1, hMLH1 and hMSH2. Thus, leukemic cells were sensitized to alkylating agents by the inhibition of MGMT.

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“…Being highly reactive molecules, the alkylating agents induce cell death by binding to DNA 10 . There are two types of alkylating drugs: monofunctional, including temozolomide and dacarbazine, which produce a cross-link between adjacent strands of DNA, and bifunctional, such as melphalan, which produces interstrand and intrastrand cross-links; melphalan also alkylates RNA and protein structures 11 . DNA lesions produced by melphalan require several and complex repair mechanisms 12 .…”

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“…Several patients presented with complete responses, although it was also recognized that the best response to TMZ is dependent on low, or absent, expression of MGMT in patients’ tumor cells [ 20 , 21 , 22 , 25 ]. The protective effect of MGMT against TMZ is particularly detrimental in AML, because the majority of AML patients present with significant MGMT expression in their tumor tissue [ 26 ], consistent with laboratory studies that only 25% of leukemia cells harbor low levels of MGMT [ 27 ], and inhibition of MGMT in vitro greatly sensitizes leukemia cells to TMZ [ 28 ].…”

Novel Xanthene-1,8-dione Derivatives Containing the Benzylic Ether Tail as Potent Cytotoxic Agents: Design, Synthesis, In Vitro, and In Silico Studies

“…As a result of alkylation, the DNA chain undergoes structural changes that afect both transcription and replication processes [3]. Temozolomide (I), carmustine (II), and cyclophosphamide (III) are three famous examples of DNA alkylating drugs (Figure 1) [4].…”