Repurposing HIV-Protease Inhibitor Precursors as Anticancer Agents: The Synthetic Molecule RDD-142 Delays Cell Cycle Progression and Induces Autophagy in HepG2 Cells with Enhanced Efficacy via Liposomal Formulation

TL;DR

A new molecule derived from an HIV drug shows promise as a cancer treatment for liver cancer by slowing cell growth and inducing cell cleanup processes.

Contribution

RDD-142, a synthetic HIV-PI precursor, is repurposed as an anticancer agent with enhanced efficacy via liposomal formulation.

Findings

RDD-142 selectively inhibits HepG2 cancer cells while sparing healthy hepatocytes.

RDD-142 induces autophagy and delays cell cycle progression via ERK1/2 pathway attenuation.

Liposomal formulation of RDD-142 enhances intracellular uptake and cytotoxic efficacy.

Abstract

Hepatocellular carcinoma (HCC) remains a global health issue due to high incidence and mortality, complicated by limited therapeutic options and evolution of de novo resistance to conventional chemotherapy. In this study, we investigated the antiproliferative activity of RDD-142, a synthetic precursor of the HIV-1 protease inhibitor (HIV-PI) Darunavir analog, on the human hepatocellular carcinoma line (HepG2) and healthy hepatocyte line (IHH), both as a free molecule and in liposomal formulation. RDD-142 demonstrated a selective cytostatic effect on HepG2, preserving healthy IHH cells. Mechanistically, RDD-142 delayed cancer cell proliferation by attenuating the ERK1/2 signaling pathway, and concurrently, it activated the autophagic process via p62 up-regulation. These effects were linked to RDD-142 inhibitory activity on the chymotrypsin-like subunit of the proteasome, triggering a UPR-mediated stress response. Notably, the liposomal formulation of RDD-142 significantly enhanced intracellular intake and cytotoxic efficacy. RDD-142 demonstrated promising potential as a therapeutic agent for HCC. Its antitumor activity may be further amplified through liposomal nanoformulation, offering a successful strategy to reduce effective dosage and minimize adverse effects.

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