A Potent Glucose–Platinum Conjugate Exploits Glucose Transporters and Preferentially Accumulates in Cancer Cells

Abstract

Three rationally designed glucose-platinum conjugates (Glc-Pts) were synthesized and their biological activities evaluated. The Glc-Pts, 1-3,exhibit high levels of cytotoxicity towardapanel of cancer cells.T he subcellular target and cellular uptake mechanism of the Glc-Pts were elucidated. For uptake into cells,G lc-Pt 1 exploits both glucose and organic cation transporters,b oth widely overexpressed in cancer. Compound 1 preferentially accumulates in and annihilates cancer,compared to normal epithelial, cells in vitro.Platinum-basedanticancerdrugs are among the most widely used of all chemotherapeutic treatments.T hree FDAapproved platinum anticancer drugs,c isplatin, carboplatin, and oxaliplatin, have been in the clinic for many years to treat av ariety of cancers including testicular,o varian, cervical, head and neck, non-small-cell lung, and colorectal. [1] Despite their success,p latinum compounds have an umber of deficiencies originating from al ack of tumor selectivity.O nly as mall fraction of the total administered platinum accumulates at the tumor site,r esulting in sub-optimal drug concentration at the target. Moreover,a ccumulation of platinum in healthy tissue leads to undesired side effects including nephrotoxicity,m yelosuppression, peripheral neuropathy, ototoxicity,a nd nausea. [1b, 2] These drawbacks need to be addressed when designing next-generation platinum drugs. Novel strategies for introducing tumor-targeting properties into platinum anticancer drug candidates are therefore of great interest. [3] In order to maintain cellular homeostasis,g rowth, and proliferation, cancer cells significantly increaseglucose uptake andt he fluxo fm etabolites throughg lycolysis.T his phenomenon, termed "the Warburg effect", arisesfrommitochondrial metabolic changesa nd is one of the hallmarkso fc ancer. [4] GLUT1,t he mostc ommon glucose transporter, is widely overexpressed in manyh uman cancersi ncludingh epatic, pancreatic,b reast,e sophageal, brain, renal, lung,c utaneous, colorectal, endometrial, ovarian,and cervical. [5] HighGLUT1 expressionl evelsi nt umor biopsy samples correlates trongly withp oorp rognosis. Moreover,s everalo ther glucose transporters including GLUT2,G LUT3,G LUT12,a nd SGLT1/2[*] Dr.

In Vitro and In Vivo Efficacy of a Novel Glucose–Methotrexate Conjugate in Targeted Cancer Treatment

“…Evidence has been found that the cellular uptake of some glycoconjugates may also be mediated by other receptors such as OCT2, SGLT, SWEET, and asialoglycoprotein receptor (ASGPR) [ 21 , 22 ]. These findings are corroborated by other studies showing that glucose conjugates exploit glucose transporters of cancer cells [ 9 , 17 ]. The uptake analysis showed that in the intracellular compartment, the payload was quickly detached from the conjugate.…”

“…GLU–MTX is transported by facilitated diffusion exploiting overexpressed GLUT1 transporters [ 17 ] and is approximately 17-times more preferentially accumulated in cancer cells compared to free MTX ( Figure 4 ). In the intracellular compartment, the cleavage of acid-labile bonds occurs, which results in the controlled release of free MTX.…”

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

“…102 Platinum(II) complexes with a DACH nonleaving group ligand and a malonate leaving group ligand attached to glucose at the 6 position via a linker of variable length were prepared and shown to be taken up selectively by GLUT1 (Chart 2E). 103 Studies with different GLUT1 inhibitors confirmed that cellular uptake was dependent on glucosylation and directly impacted cell-killing efficacy. An interesting effect of chain length on uptake via GLUT1 was observed and modelling studies indicate that an overly long linker between the glucose and the platinum inhibits the ability of the protein to undergo the conformational change required to transport the construct across the cell membrane.…”

“…The organic cation transporters were also found to play a role in the uptake and efficacy of the most potent of the glucoconjugates prepared. 103 …”

Selective Targeting of Cancer Cells by Copper Ionophores: An Overview

“…As a consequence, glucose transporters (i.e., GLUT1) are overexpressed in several human cancers (Szablewski, 2013). Just to give a few examples, anticancer platinum (Pt) systems with appended glucose moieties were active against a panel of cancer cells and accumulated preferentially in tumor cells compared to normal cells (Patra et al, 2016b;Ma et al, 2016). Moreover, an elegant SAR study has demonstrated that the conjugation of the Pt moiety to different positions of D-glucose influences the cellular uptake mediated by GLUT and cytotoxicity of the glycoconjugates (Patra et al, 2016a).…”