Rhenium Perrhenate (<sup>188</sup>ReO<sub>4</sub>) Induced Apoptosis and Reduced Cancerous Phenotype in Liver Cancer Cells
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
Affiliations
Samieh Asadian
Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin 34199153, Iran
Abbas Piryaei
Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 16123798, Iran
Nematollah Gheibi
Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin 34199153, Iran
Bagher Aziz Kalantari
Department of Organic Chemistry, Karaj Branch, Islamic Azad University, Karaj 16255879, Iran
Mohamad Reza Davarpanah
Faculty of Nuclear Engineering, Shahid Beheshti University, Tehran 15689456, Iran
Mehdi Azad
Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin 34199153, Iran
Valentina Kapustina
Department of Internal Medicine N1, Sechenov University, 119991 Moscow, Russia
Mehdi Alikhani
Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 16635148, Iran
Sahar Moghbeli Nejad
Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin 34199153, Iran
Hani Keshavarz Alikhani
Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 16635148, Iran
Morteza Mohamadi
Department of Physical Chemistry, Faculty of Science, University of Tehran, Tehran 17456987, Iran
Anastasia Shpichka
World-Class Research Center “Digital Biodesign and Personalized Healthcare”, Sechenov University, 119991 Moscow, Russia
Peter Timashev
World-Class Research Center “Digital Biodesign and Personalized Healthcare”, Sechenov University, 119991 Moscow, Russia
Moustapha Hassan
Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, 141-83 Stockholm, Sweden
Massoud Vosough
Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 16635148, Iran
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.
