Stem Cell-Derived Exosomes Significantly Boost Etoposide-Induced Apoptosis in HepG2 Liver Cancer Cells: A Novel Strategy for Enhanced Chemotherapy

Background: Hepatocellular carcinoma (HCC) is the most prevalent type of liver malignancy worldwide. Traditional cancer treatments, such as chemotherapy and radiotherapy, often pose significant risks, including potential organ damage and, in severe cases, death. Etoposide (ETO), a commonly used chemotherapeutic agent, is not exempt from these complications. Combinational therapies have been explored for years as promising strategies to enhance treatment efficacy while mitigating adverse side effects. Stem cell-derived exosomes, recognized for their therapeutic potential, have emerged as valuable tools in cancer treatment due to their anti-cancer properties. Objectives: The present study investigates the potential synergistic effects between stem cell-derived exosomes and ETO in inducing apoptosis in HepG2 HCC cells. Methods: Cell apoptosis was evaluated using Annexin V/PI staining along with caspase-3 and -9 activity assays. Gene expression of Bax and Bcl-2 was measured by qRT-PCR, while p53 protein levels were assessed using western blotting. Results: Treatment with both stem cell-derived exosomes (100 µg/mL) and ETO (10 µM) significantly reduced HepG2 cell viability and induced apoptosis (16.2%) compared to either treatment alone. Caspase-9 and -3 activities increased to 69% and 64%, respectively, under combined treatment, versus 33% and 31% with exosomes and 51% and 39% with ETO alone. Bax expression rose by 3.6-fold, and Bcl-2 decreased to 0.44-fold upon co-treatment, leading to a markedly elevated Bax/Bcl-2 ratio. Moreover, p53 protein levels increased 3.24-fold, highlighting the enhanced apoptotic signaling. These results confirm a synergistic effect between exosomes and ETO. Conclusions: Our findings reveal that stem cell-derived exosomes exhibit synergistic effects when co-treated with ETO in HepG2 cells. Building on these results, we conclude that further investigation of this combination could lead to the development of a promising anti-cancer therapy for HCC.