Glutor, a Glucose Transporter Inhibitor, Exerts Antineoplastic Action on Tumor Cells of Thymic Origin: Implication of Modulated Metabolism, Survival, Oxidative Stress, Mitochondrial Membrane Potential, pH Homeostasis, and Chemosensitivity

Abstract

Neoplastic cells overexpress glucose transporters (GLUT), particularly GLUT1 and GLUT3, to support altered metabolism. Hence, novel strategies are being explored to effectively inhibit GLUTs for a daunting interference of glucose uptake. Glutor, a piperazine-2-one derivative, is a newly reported pan-GLUT inhibitor with a promising antineoplastic potential. However, several aspects of the underlying mechanisms remain obscure. To understand this better, tumor cells of thymic origin designated as Dalton’s lymphoma (DL) were treated with glutor and analyzed for survival and metabolism regulatory molecular events. Treatment of tumor cells with glutor caused a decrease in cell survival with augmented induction of apoptosis. It also caused a decrease in glucose uptake associated with altered expression of GLUT1 and GLUT3. HIF-1α, HK-2, LDH-A, and MCT1 also decreased with diminished lactate production and deregulated pH homeostasis. Moreover, glutor treatment modulated the expression of cell survival regulatory molecules p53, Hsp70, IL-2 receptor CD25, and C-myc along with mitochondrial membrane depolarization, increased intracellular ROS expression, and altered Bcl-2/BAX ratio. Glutor also enhanced the chemosensitivity of tumor cells to cisplatin, accompanied by decreased MDR1 expression. Adding fructose to the culture medium containing glutor reversed the latter’s inhibitory action on tumor cell survival. These results demonstrate that in addition to inhibited glucose uptake, modulated tumor growth regulatory molecular pathways are also implicated in the manifestation of the antineoplastic action of glutor. Thus, the novel findings of this study will have a long-lasting clinical significance in evaluating and optimizing the use of glutor in anticancer therapeutic strategies.

Targeting the Warburg Effect in Cancer: Where Do We Stand?

“…Other GLUT inhibitors, such as BAY-876, exhibit the capacity to impede the growth of triple-negative breast cancer in patient-derived xenograft models [ 82 ]. Additionally, Glutor, a pan-GLUT inhibitor, has also been reported to exert antineoplastic effects [ 59 ]. Notably, the inhibition of GLUT1 induces cell death, overcoming resistance to chemotherapeutic agents in cultured gastrointestinal cell lines [ 83 ] and sensitizing radio-resistant breast cancer cells [ 84 ].…”

An appraisal of the current status of inhibition of glucose transporters as an emerging antineoplastic approach: Promising potential of new pan-GLUT inhibitors

“…Recently a pan-GLUT inhibitor named glutor has been demonstrated to exhibit a potent antineoplastic action in the nanomolar concentration range against cancer cells of diverse origins ( Reckzeh and Waldmann, 2020a ; Reckzeh and Waldmann, 2020b ; Temre et al, 2022 ). Glutor is (S)-6-Methyl-5-(4-morpholinobenzyl)-4-oxo-2-phenyl-N-(pyridin-3-ylmethyl)-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-6-carboxamide, with the empirical formula C 3 H 32 N 6 O 3 , and molecular weight of 536.62 ( Figure 5F ) ( Reckzeh et al, 2019 ).…”

“…Additionally, glutor treatment triggered mitochondrial membrane depolarization, accompanied by high ROS generation and the modulated ratio of Bcl-2/BAX. Chemosensitivity of tumor cells increased following exposure to glutor and decreased MDR1 expression ( Temre et al, 2022 ). Hence, these observations indicate that glutor has the potential to be used in antineoplastic therapeutic applications.…”

“…Moreover, several studies have been conducted to evaluate the outcome of combining various GLUT inhibitors for achieving optimum inhibition of glucose uptake ( Tilekar et al, 2020 ). The most promising of such combinations with successful antineoplastic outcomes include combination of GLUT inhibitors like cytochalasin B, WZB117 and its derivatives, BAY-876, silibinin, glutor, STF-31 and phloretin with other conventional anticancer drugs like doxorubicin, curcumin, etoposide, cisplatin, 5-fluorouracil, vincristine, cytarabine, oxaliplatin, paclitaxel and antimycin A ( Liu et al, 2012 ; Tsakalozou et al, 2012 ; Li et al, 2019 ; Trendowski, 2015 ; Trendowski, 2015 ; Kapoor et al, 2016 ; Chen et al, 2017 ; Reckzeh et al, 2019 ; Zambrano et al, 2019 ; Barbosa and Martel, 2020 ; Joly et al, 2020 ; Tilekar et al, 2020 ; Wu et al, 2020 ; Shriwas et al, 2021 ; Olszewski et al, 2022 ; Temre et al, 2022 ; Weng et al, 2022 ) to name a few such representative anticancer drugs in cancers of diverse origins. Nevertheless, inhibitors of other molecules and/or pathways have also been combined with GLUT inhibitors to achieve fruitful antineoplastic effects ( Tsakalozou et al, 2012 ; Tilekar et al, 2020 ; Weng et al, 2022 ).…”

Blockade of phosphodiesterase 5 by sildenafil reduces tumor growth and potentiates tumor‐killing ability of cisplatin in vivo against T cell lymphoma: Implication of modulated apoptosis, reactive oxygen species homeostasis, glucose metabolism, and pH regulation

“…Given the facts considered above, the present study was planned to understand the tumor growth decelerating and chemosensitizing action of SDF in a murine model of T cell lymphoma designated as Dalton's lymphoma (DL). The DL is a transplantable murine T cell lymphoma of spontaneous origin, 25 which has been extensively used to determine the antineoplastic and chemosensitizing action of several synthetic and plant-derived chemicals [26][27][28][29] and for delineating the host-tumor relationship. [30][31][32] The present study investigates the tumor growth retarding and survival prolonging effect of SDF in DL-bearing murine hosts.…”