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

It is a decade-long controversy that transarterial chemoembolization (TACE) has definite priority over transarterial embolization (TAE) in treating patients with hepatocellular carcinoma (HCC), since HCC cells are regularly resistant to chemotherapy by enhanced expression of proteins that confer drug resistance, and ABC transporters pump the intracellular drug out of the cell. We addressed this issue by modulating the chemo-environment. In an animal model, sevelamer, a polymeric phosphate binder, was introduced as an embolic agent to induce intratumoral inorganic phosphate (Pi) starvation, and trans-arterially co-delivered with doxorubicin (DOX). The new type of TACE was named as DOX-TASE. This Pi-starved environment enhanced DOX tumoral accumulation and retention, and DOX-TASE thereby induced more severe tumor necrosis than that induced by conventional TACE (C-TACE) and drug-eluting bead TACE (D-TACE) at the same dose. In vitro tests showed that Pi starvation increased the cellular accumulation of DOX in an irreversible manner and enhanced cytotoxicity and cell apoptosis by suppressing the expression of ABC transporters (P-glycoprotein (P-gp), BCRP, and MRP1) and the production of intracellular ATP. Our results are indicative of an alternative interventional therapy combining chemotherapy with embolization more effectively.

Automated summary

This study proposes a new method for treating hepatocellular carcinoma (HCC) using transarterial chemoembolization (TACE), called DOX-TASE. By modulating the chemo-environment with sevelamer, a polymeric phosphate binder, intratumoral inorganic phosphate (Pi) starvation is induced, resulting in increased accumulation and retention of the chemotherapy drug doxorubicin (DOX) in the tumor. This new approach induces more severe tumor necrosis compared to conventional TACE and drug-eluting bead TACE.