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Repurposing HIV-Protease Inhibitor Precursors as Anticancer Agents: The Synthetic Molecule RDD-142 Delays Cell Cycle
Fabiana Crispo1, Antonio Vassallo2, Immacolata Faraone2
1Laboratory of Preclinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy.
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.
Insights
RDD-142, a novel compound, selectively inhibits hepatocellular carcinoma (HCC) cell growth by targeting cancer cell proliferation pathways. Liposomal RDD-142 enhances efficacy, offering a promising therapeutic strategy for HCC treatment.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Hepatocellular carcinoma (HCC) presents significant global health challenges with limited treatment options.
- Drug resistance and high mortality rates necessitate novel therapeutic approaches for HCC.
Purpose of the Study:
- To investigate the antiproliferative effects of RDD-142, a synthetic precursor of a Darunavir analog, on HCC.
- To evaluate the efficacy of RDD-142 in both free and liposomal formulations on HepG2 and healthy IHH cells.
Main Methods:
- Assessing the selective cytostatic activity of RDD-142 on HepG2 and IHH cell lines.
- Investigating the molecular mechanisms, including ERK1/2 signaling, autophagy, and proteasome inhibition.
- Comparing the efficacy of free RDD-142 versus its liposomal formulation.
Main Results:
- RDD-142 exhibited selective antiproliferative effects on HepG2 cells, sparing healthy IHH cells.
- The compound attenuated ERK1/2 signaling, upregulated p62-mediated autophagy, and inhibited proteasome activity.
- Liposomal RDD-142 significantly enhanced cellular uptake and cytotoxic efficacy compared to the free molecule.
Conclusions:
- RDD-142 shows potential as a therapeutic agent for hepatocellular carcinoma.
- Liposomal nanoformulation can amplify RDD-142's antitumor activity, potentially reducing dosage and adverse effects.
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