Genetic polymorphisms potentially associated with response to metformin in postmenopausal diabetics suffering and not suffering with cancer

Abstract

Metformin is a well-known antidiabetic medication, which, besides diabetes, may be involved into modulation of other age-related pathologies, including cancer. The study concerns 12 gene polymorphisms divided into 2 groups consisting of 6 genes each. The first group was composed from so-called "standard" (S) polymorphisms, for which the connection with metabolic response to metformin is already established. The second group included polymorphisms of genes encoding proteins possibly connected with diabetes mellitus type 2 (DM2), impaired glucose tolerance or cancer and entitled here as "associated" (A). A total of 156 postmenopausal women (average age 60.7 ± 0.7) were included, 37 of them healthy, 64 with type DM2 and concurrent treatment-naïve cancer (mostly breast, endometrial or colorectal cancer), 32 with DM2 without cancer, and 23 with treatment-naïve cancer and normal glucose tolerance. The leading metformin response S-marker in combined group of DM2 patients was the CC variant of OCT1-R61C polymorphism of organic cation transporter protein 1 gene. In cancer patients without DM2, this position belonged to AC and AA genotypes of OCT1_rs622342 polymorphism. Among the A-polymorphisms, GA variant of sex hormone-binding globulin gene SHBG_D356N was less frequently observed in DM2 patients with or without cancer. Besides, in diabetics, the same polymorphic variant of SHBG as well as GC genotype of oxidized lipoprotein receptor OLR1_G501C and GG genotype of locus rs11065987 near BRAP gene were carried rather often in combination with "metformin-positive" variant of OCT1_R61C. In addition, carriers of OCT1_R61C and OCT1_rs622342 polymorphisms with potentially positive reaction to metformin had higher insulin resistance score (HOMA-IR) values. Received data lead to the conclusion that postmenopausal diabetics, both with and without cancer, differ in genetic stigmata of potential response to metformin less than they differ from cancer patients without DM2. As genetic polymorphisms associated with metabolic and anticancer metformin (and, possibly, phenformin) effects may be different, this subject requires further investigation.

Metformin and Colorectal Cancer – A Systematic Review.

“…Another study confirmed pro-apoptotic properties of metformin treatment at near-pharmacological levels (60 µmol/L), which acted by induction of proapoptotic genes and increased apoptosis of HCT116 cell line [30]. The effectiveness of metformin may be associated with a genetic polymorphism in patients with diabetes [31]. Only one study did not confirm the ef-fect of metformin used alone on inhibition of cell proliferation and induction of apoptosis in 3 CRC cell lines treated with 3 concentrations of metformin (1, 5, and 10 mmol/L) [32].…”

Breast Cancer Metabolism and Mitochondrial Activity: The Possibility of Chemoprevention with Metformin

“…In order to inhibit mitochondrial complex I and consequently decrease tumorigenesis, cancer cells need a robust inner mitochondrial membrane potential to allow metformin to reach the mitochondrial matrix. It is therefore possible to hypothesize that metformin efficacy as an anticancer agent depends on the tumor expression of OCTs and a recent work [ 83 ] has shown that the selectivity of metformin response may be due to hormonal, metabolic, and associated genetic factors, including some allelic polymorphisms related to OCTs. Moreover, cancer heterogeneity of OCT1, and hence for cancer cell uptake of metformin, could be assessed before considering metformin therapy in the clinical and prevention setting given, for example, the low expression of OCT1 in normal breast tissues.…”

Hormonal, metabolic and genetic predictors of metformin efficacy in patients with diabetes mellitus and cancer

“…В случае последних речь идет преимущественно о полиморфных вариантах генов, кодирующих белки, ассоциированные с утилизацией/ метаболизмом метформина и механизмом его действия (см. более подробно в работах [8,9] и ниже). В отношении предикторов возможного противоопухолевого действия метформина (в особенности, в том случае, когда опухо-левая ткань для анализа недоступна) вопрос находится на достаточно ранней стадии своего изучения [9,10].…”

“…ДНК выделяли соль-хлороформным методом, генотипирование проводили при помощи ал-лель-специфической полимеразной цепной реакции (ПЦР) в режиме реального времени на приборе iQ iCycler (Bio-Rad) с использованием интеркалирующего краси-теля SYBR Green I. Праймеры, их температуры отжига и длины синтезированных фрагментов для анализа по-лиморфизма соответствующих генов приведены в ра-боте [9]. ПЦР-амплификация проходила в объеме 20 …”

“…1). В последнем случае это может быть объяснено тем обстоятельством, что хотя только что упомянутый генотип GA был отнесен нами на основании некоторых косвенных данных к мар-керам МФ+ ответа [9], носительство этого полиморф-ного варианта одновременно сопряжено со снижением риска развития СД2 [15].…”