Rhenium Perrhenate (¹⁸⁸ReO₄) Induced Apoptosis and Reduced Cancerous Phenotype in Liver Cancer Cells

• Published in: Cells
• Main Authors: Samieh Asadian, Abbas Piryaei, Nematollah Gheibi, Bagher Aziz Kalantari, Mohamad Reza Davarpanah, Mehdi Azad, Valentina Kapustina, Mehdi Alikhani, Sahar Moghbeli Nejad, Hani Keshavarz Alikhani, Morteza Mohamadi, Anastasia Shpichka, Peter Timashev, Moustapha Hassan, Massoud Vosough
• Format: Article
• Language: English
• Published: MDPI AG 2022-01-01
• Subjects: hepatocellular carcinoma; apoptosis induction; cell cycle arrest; Rhenium-188 (¹⁸⁸Re); radionuclide therapy
• Online Access: https://www.mdpi.com/2073-4409/11/2/305
• ISSN: 2073-4409

Recurrence in hepatocellular carcinoma (HCC) after conventional treatments is a crucial challenge. Despite the promising progress in advanced targeted therapies, HCC is the fourth leading cause of cancer death worldwide. Radionuclide therapy can potentially be a practical targeted approach to address this concern. Rhenium-188 (¹⁸⁸Re) is a β-emitting radionuclide used in the clinic to induce apoptosis and inhibit cell proliferation. Although adherent cell cultures are efficient and reliable, appropriate cell-cell and cell-extracellular matrix (ECM) contact is still lacking. Thus, we herein aimed to assess ¹⁸⁸Re as a potential therapeutic component for HCC in 2D and 3D models. The death rate in treated Huh7 and HepG2 lines was significantly higher than in untreated control groups using viability assay. After treatment with ¹⁸⁸ReO₄, Annexin/PI data indicated considerable apoptosis induction in HepG2 cells after 48 h but not Huh7 cells. Quantitative RT-PCR and western blotting data also showed increased apoptosis in response to ¹⁸⁸ReO₄ treatment. In Huh7 cells, exposure to an effective dose of ¹⁸⁸ReO₄ led to cell cycle arrest in the G2 phase. Moreover, colony formation assay confirmed post-exposure growth suppression in Huh7 and HepG2 cells. Then, the immunostaining displayed proliferation inhibition in the ¹⁸⁸ReO₄-treated cells on 3D scaffolds of liver ECM. The PI3-AKT signaling pathway was activated in 3D culture but not in 2D culture. In nude mice, Huh7 cells treated with an effective dose of ¹⁸⁸ReO₄ lost their tumor formation ability compared to the control group. These findings suggest that ¹⁸⁸ReO₄ can be a potential new therapeutic agent against HCC through induction of apoptosis and cell cycle arrest and inhibition of tumor formation. This approach can be effectively combined with antibodies and peptides for more selective and personalized therapy.