Low Inorganic Phosphate Stress Inhibits Liver Cancer Progression: from In Vivo to In Vitro

Abstract

Metabolic stress (for example, low pO 2 , low pH) stimulates cancer progression in a complex and largely unresolved manner. Excessive inorganic phosphate burden is being considered as another stimulator, until now there is no well-designed study to examine the potential benefits of reducing phosphate burden on cancer progression. Sevelamer microspheres, a polymeric phosphate binder, are introduced as embolic material for interventional treatment of rabbit VX2 liver cancer model. This technique is named as "transarterial sevelamer embolization (TASE)." The microspheres prove to be highly biocompatible, and TASE is found to be a safe local-regional technique. Compared with conventional transarterial chemoembolization (TACE), TASE is found to not only occlude the tumor-feeding vessel, but simultaneously deplete intratumoral inorganic phosphate (Pi), thereby inducing severe necrosis as well reducing metastasis and recurrence. Reduced Pi stress inhibits tumor vascularity, invasion, and metastasis by downregulating the angiogenic factors and oncoprotein expression. Energy metabolomics indicate that Pi stress also suppresses tumor anaerobic glycolysis and glutaminolysis. This systemic anti-cancer effect indicates a promising new application for sevelamer and TASE as a potential alternative to conventional TACE for liver cancer treatment.

Intratumoral Pi deprivation benefits chemoembolization therapy via increased accumulation of intracellular doxorubicin

“…All the in vitro tests identified that Pi starvation irreversibly increased the cellular influx of DOX as the expression of three common MDR plasma membrane proteins driving the efflux of drugs (P-gp, BCRP, and MRP1) was effectively impaired as Pi stress led to downregulated expression levels of ABC transporter genes, which has been reported to influence the efficacy of chemotherapy in patients with HCC (Korita et al., 2010 ). As we proved, those MDR proteins are less expressed in the Pi-deprived environment, and ATP is also less produced, which is consistent with our recent findings evidenced by metabolomics (Bi et al., 2022 ). In other words, there is a lack of both ‘vehicles’ and ‘gas’, and intracellular drugs cannot be passively transported out and must remain inside the cell.…”

“…Drug resistance is very complex and modulated by genetic and epigenetic alterations that affect drug uptake, metabolism, and export of drugs at the cellular level. As chemical characteristics of the tumor microenvironment, hypoxia and acidity influence the sensitivity of the tumor cells to drug treatment (Tredan et al., 2007 ), and we have found that low Pi stress induces some anticancer effects (Bi et al., 2022 ). Therefore, intratumoral Pi starvation might inhibit or retard those pathways beneficial for drug resistance.…”

“…Based on the concept of Pi deprivation as a new anticancer strategy, we have proposed TASE as an alternative embolization technique to treat HCC in the rabbit VX2 model (Bi et al., 2022 ). Herein, we utilize this strategy to overcome and reverse drug resistance to enhance TACE therapy via promoting the increased accumulation of intracellular DOX.…”

“…Moreover, glucose has been proven to sensitize HCC cells to DOX and sorafenib (Chouhan et al., 2020 ). Our recent work illustrated the transarterial sevelamer embolization (TASE) technique, which promotes intratumoral inorganic phosphate (Pi) starvation (Bi et al., 2022 ). It is expected that drug resistance might be reversed as Pi starvation induces less ATP production from VX2 cancer cells, since ATP consumption is required to pump the intracellular drug out of the cell.…”

Evaluation of the safety and efficacy of transarterial sevelamer embolization in a rabbit liver cancer model: A challenge on the size rule for vascular occlusion

“…Recently we try to introduce an aggregation-responsive particulate embolic agent. In detail, sevelamer ultrafine particle was developed as a highly mobile embolic polymer for chemoembolization therapy, the small particles maximally fill the target artery, as they are ready to aggregate into big particles with the tunable size of hundreds of micrometers by the activation of endogenous inorganic phosphate (Pi), thereby expecting to avoid inter or intrahepatic distribution ( Bi et al, 2021 ). Here we would give evidence of this permeability and challenge the traditional “40 μm” rule by analyzing the specimen after embolization.…”