Effect of interaction of glutathione S-transferases (T1 and M1) on the hematologic and cytogenetic responses in chronic myeloid leukemia patients treated with imatinib

Abstract

The glutathione S-transferases (GSTs) are phase II xenobiotic metabolizing enzymes known to be involved in the detoxification of carcinogens and anticancer drugs. Individual genetic variation linked to inherited polymorphisms of GSTT1 and GSTM1 leading to a complete loss of enzyme activity could expose subjects to develop cancer or to induce drug resistance. Indeed, despite the impressive results obtained with the imatinib, some patients with chronic myeloid leukemia (CML) fail to achieve the expected results or develop resistance. The present study aimed to examine the impact of GSTT1 and GSTM1 polymorphisms on the response to imatinib in patients with CML. Multiplex polymerase chain reaction was used to detect the genotypes of GSTT1 and GSTM1 in 60 CML patients. We found that side effects were more frequent in patients carrying GSTT1 null when compared to GSTT1 present carriers (31 vs. 16.6 %; χ (2) = 6.2; p = 0.013). The loss of hematologic response was statistically greater in patients carrying the combined genotype GSTT1 present/GSTM1 present (26.3 %) when compared to GSTT1 null/GSTM1 present (12.8 %), GSTT1 present/GSTM1 null (8.3 %) and GSTT1 null/GSTM1 null (0 %), (χ (2) = 18.85; p < 0.001). The complete cytogenetic response was higher in patients harboring the GSTT1 null/GSTM1 null (75 %) compared with GSTT1 null/GSTM1 present (55.6 %), GSTT1 present/GSTM1 null (50 %) and GSTT1 present/GSTM1 present (47.8). On the other hand, the frequency of none cytogenetic responders was more common in patients carrying GSTT1 present/GSTM1 present (34.8 %) when compared to other genotype combinations (χ (2) = 20.99; p = 0.05). Moreover, the GSTT1 present/GSTM1 present appeared to be associated with a final dose of 600 or 800 mg of imatinib, but not significantly. Based on these findings, we find that the interaction between GSTT1 and GSTM1 seems to influence treatment outcome in patients with CML. Therefore, further investigations are required to confirm these results, for better genotype-phenotype correlation.

Influence of glutathione S‐transferases (GSTM1, GSTT1, and GSTP1) genetic polymorphisms and smoking on susceptibility risk of chronic myeloid leukemia and treatment response

“…Chronic myeloid leukemia (CML) is a myeloproliferative disease and an outcome of the reciprocal translocation t (9;22) (q34;q11) or the BCR-ABL1 fusion gene (Kassogue et al, 2014;Rostami, Hamid, Yaran, Khani, & Karimipoor, 2015). The tyrosine kinase inhibitor (TKI), Imatinib mesylate (IM) is a potent Bcr-Abl1-targeting drug with remarkable clinical benefits.…”

“…Whole-gene deletion polymorphisms of GSTM1 (OMIM accession number: *138350) and GSTT1 (OMIM accession number:*600436) genes and the single nucleotide polymorphism (SNP) in GSTP1 c. 313 A>G ( p. 105Ile>Val; rs1695) (OMIM accession number:*134660) lead to the absence or decreased detoxification ability of enzymes, their dysfunction, and finally may impact on the risk of cancer development, heterogeneous drug responsiveness (Davies et al, 2014;Hollman, Tchounwou, & Huang, 2016;Özten et al, 2012). Several studies determined only the role of GST polymorphisms on CML susceptibility (Al-Achkar, Azeiz, Moassass, & Wafa, 2014;He et al, 2014;Özten et al, 2012) and some studies assessed their impact on treatment response (Davies et al, 2014;Kassogue et al, 2014). A recent study has evaluated the effect of GST polymorphisms on CML susceptibility and treatment response, but the interaction between these genes and environmental exposures or risk factors such as cigarette smoke was not evaluated in CML development (Weich et al, 2016).…”

Glutathione S-transferase M1 and T1 genes deletion polymorphisms and risk of developing essential hypertension: a case-control study in Burkina Faso population (West Africa)

“…There were several studies about GSTM1 and GSTT1 deletion and some diseases process, so Fig. 1 summarizes the frequencies of the GSTM1 and GSTT1 deletion in some African countries [37][38][39][40][41][42][43][44][45][46]. In our study we analyzed also the relationship between Glutathione S-transferase M1 and T1 genes deletion and their connection with essential hypertension and any complications that may have accompanied this disease in Burkina Faso.…”

“…GSTM1 and GSTT1 genes deletion frequency in African countries[37][38][39][40][41][42][43][44][45][46]. Legend: Pie charts show frequency of GSTM1-null (red) and GSTT1null (yellow) frequency in each country…”

Genetic polymorphism of drug metabolism enzymes (GSTM1, GSTT1 and GSTP1) in the healthy Malian population

“…The PCR reaction mixture consisted of 100 ng of genomic DNA, 1× of 10× Buffer (Invitrogen), 1.5 mM of MgCl2, 0.2 mM of each dNTP, 10 pM of each primer and 0.5 U of Taq polymerase (Invitrogen) completed to 25 µL with molecular grade water. The forwards and reverses primers used for GSTT1, GSTM1 and BCL2 as well as PCR amplification technical aspects were previously described in details by Kassogue et al [21,22]. DNA fragments were analyzed on a 2% agarose gel stained with 0.5 µg/mL ethidium bromide.…”