Advancing hepatic cell carcinoma treatment through mitochondrial DNA targeting

Hepatic cell carcinoma (HCC), the fifth most prevalent malignancy worldwide and the fourth leading cause of cancer-related mortality, poses significant therapeutic challenges. Despite advancements in medical research, late-stage HCC patients have a dismal five-year survival rate of less than 20%. The complexity of liver cancer development involves an intricate interplay of genetic and environmental factors. Among these, mitochondrial alterations and mutations in mitochondrial DNA (mtDNA) are increasingly recognized as critical contributors to cancer pathogenesis. These changes not only impair cellular bioenergetics but also influence tumor suppressors and oncogenic proteins, exacerbating the malignancy. Consequently, targeting mitochondrial dysfunction and mtDNA mutations has emerged as a promising therapeutic strategy.

Mitochondria are pivotal for energy production, metabolism, and cell signaling in eukaryotic cells. They contain their own DNA, mtDNA, which encodes essential proteins for oxidative phosphorylation and ATP synthesis. Human mtDNA is a small, circular, double-stranded genome, approximately 16.6 kbp in size, and is maternally inherited. MtDNA comprises three regions: the coding region, the D-loop region, and the non-coding region. The coding region includes 37 genes crucial for mitochondrial protein translation, while the D-loop region regulates mtDNA replication and transcription.

Mitochondrial dysfunction in HCC involves excessive production of reactive oxygen species (ROS) and defects in mitochondrial enzymes. These dysfunctions can lead to altered cellular metabolism and contribute to the progression of cancer. Additionally, changes in microRNA levels have been linked to mtDNA dysfunction and ROS generation, further complicating the cellular environment.

Recent research has focused on various pharmacological approaches to target mitochondrial dysfunction in cancer. One approach involves targeting the electron transport chain (ETC), responsible for ATP production in mitochondria. Inhibiting transcription of proteins involved in mitochondrial biogenesis pathways is another strategy. These therapeutic interventions aim to restore normal mitochondrial function and prevent cancer progression.

One promising area of research is the role of adenosine monophosphate-activated protein kinase (AMPK) in regulating mitochondrial function. AMPK-dependent inhibition of proteins such as NFκB, p38, and ERK1/2 has shown potential in reducing cancer cell proliferation. For instance, the antiplatelet drug cilostazol inhibits hepatic cancer cell proliferation via AMPK and AKT/ERK signaling pathways. Similarly, the anesthetic propofol has been found to inhibit HepG2 cell proliferation by activating AMPK signaling.

Understanding the role of mtDNA in cancer pathogenesis is crucial for developing targeted therapies. mtDNA mutations have been identified as triggering factors in tumor formation, indicating a direct causal relationship. Targeting mtDNA offers a novel approach in cancer therapy, providing insights into cellular responses to mtDNA damage, predicting treatment efficacy, and assessing potential drug resistance.

Recent advancements in mtDNA-targeted therapies have shown promise, with several therapeutic candidates undergoing clinical trials for various cancers. However, there is a notable lack of clinical studies specifically assessing the efficacy of mitochondrial-targeted therapies in HCC. Future research should focus on the activation or inactivation of AMPK in a context-dependent manner to develop innovative treatment regimens for mitigating cancer development.

Despite the complexities of mitochondrial dysfunction and the multifaceted nature of its mechanisms, further exploration into plant-derived anticancer agents and other natural products could yield valuable therapeutic options. This review aims to provide insights that may inform future research and facilitate the development of novel medications and methods targeting mtDNA.

Mitochondrial DNA targeted therapy represents a promising frontier in the treatment of hepatic cell carcinoma. By understanding the intricate role of mtDNA in cancer progression and leveraging this knowledge to develop targeted therapies, we can pave the way for more effective and personalized treatment options for HCC patients. Continued research and clinical trials are essential to fully realize the potential of mtDNA-targeted therapies and improve outcomes for those battling this challenging disease.