Counteracting Action of Curcumin on High Glucose-Induced Chemoresistance in Hepatic Carcinoma Cells

Abstract

Along with direct anticancer activity, curcumin hinders the onset of chemoresistance. Among many, high glucose condition is a key driving factor for chemoresistance. However, the ability of curcumin remains unexplored against high glucose-induced chemoresistance. Moreover, chemoresistance is major hindrance in effective clinical management of liver cancer. Using hepatic carcinoma HepG2 cells, the present investigation demonstrates that high glucose induces chemoresistance, which is averted by the simultaneous presence of curcumin. Curcumin obviated the hyperglycemia-induced modulations like elevated glucose consumption, lactate production, and extracellular acidification, and diminished nitric oxide and reactive oxygen species (ROS) production. Modulated molecular regulators are suggested to play a crucial role as curcumin pretreatment also prevented the onset of chemoresistance by high glucose. High glucose instigated suppression in the intracellular accumulation of anticancer drug doxorubicin and drug-induced chromatin compactness along with declined expression of drug efflux pump MDR-1 and transcription factors and signal transducers governing the survival, aggressiveness, and apoptotic cell death (p53, HIF-1α, mTOR, MYC, STAT3). Curcumin alleviated the suppression of drug retention and nuclear condensation along with hindering the high glucose-induced alterations in transcription factors and signal transducers. High glucose-driven resistance in cancer cells was associated with elevated expression of metabolic enzymes HKII, PFK1, GAPDH, PKM2, LDH-A, IDH3A, and FASN. Metabolite transporters and receptors (GLUT-1, MCT-1, MCT-4, and HCAR-1) were also found upregulated in high glucose exposed HepG2 cells. Curcumin inhibited the elevated expression of these enzymes, transporters, and receptors in cancer cells. Curcumin also uplifted the SDH expression, which was inhibited in high glucose condition. Taken together, the findings of the present investigation first time demonstrate the ability of curcumin against high glucose-induced chemoresistance, along with its molecular mechanism. This will have implication in therapeutic management of malignancies in diabetic conditions.

Bioinformatics screening the novel and promising targets of curcumin in hepatocellular carcinoma chemotherapy and prognosis

“…Lee and his college reported that no cytotoxicity was observed in HepG2 cells when curcumin was not more than 20 μM for 48 h treatment [ 60 ]. But Soni and his college reported that 10 μM curcumin sufficiently and significantly decreased the cell viability of HepG2 cells [ 61 ]. In line with Lee’ s result, our results showed that the lower dose (from 0 μM to 10 μM) curcumin has no significant effect on decreasing cellular viability of HepG2.2 cells.…”

Phytocompounds curcumin, quercetin, and resveratrol modulate lactate pyruvate level in U87 glioma cells

“…17 Curcumin has been shown to affect metabolism, resulting in lower glucose absorption and lactate generation. 18 Changes in metabolic pathways, particularly fatty acid metabolism, have been linked to phytocompounds such as resveratrol, quercetin, and epicatechin gallate. Our results show quercetin, curcumin and resveratrol, induce metabolic changes in Glioma cells.…”

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

“… Vick et al (1973) introduced the first herbal GLUT inhibitor named “Phlorizin,” which was followed by a series of discoveries of several other GLUT inhibitors of plant origin which belong to various chemical categories, including alkaloids, flavonoids, and other oxygen heterocyclic and phenolic compounds ( Shriwas et al, 2020 ). Among these diverse categories of GLUT inhibitors of plant origin, those identified with antineoplastic action include more than 25 compounds, to name a few of them: apigenin ( Gonzalez-Menendez et al, 2014 ), curcumin ( Gunnink et al, 2016 ; Soni et al, 2021 ), genistein ( Vera et al, 1996 ; Pérez et al, 2011 ), naringenin ( Memariani et al, 2021 ), oridonin ( Yao et al, 2017 ), phloretin ( Wu et al, 2018 ; Wang et al, 2022 ), phlorizin ( Vick et al, 1973 ; Kwon and Levine, 2007 ; Shriwas et al, 2020 ), quercetin ( Schmidl et al, 2021a ), resveratrol ( Jung et al, 2013 ; Gwak et al, 2015 ; Zambrano et al, 2019 ; Samec et al, 2020 ), silybin ( Zhan et al, 2011 ), and vinblastine ( Shriwas et al, 2020 ). Although many of these GLUT inhibitors display a promising antineoplastic potential, the precise mechanism of the inhibitory action of most remains elusive, which needs to be deciphered for their optimal utilization in antineoplastic therapeutics.…”