Simultaneous Inhibition of ACLY and OGDH Has a Synergistic Effect on Hepatocellular Carcinoma Cell Lines
Mehdi Dehghan Manshadi1,2,3, Nagesh Kishan Panchal4, Lu-Zhe Sun4,5
1Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Abstract:
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide. Current treatments offer limited efficacy and no definitive cure, underscoring the urgent need for more selective and effective therapeutic strategies. This study investigated the synthetic lethality caused by co-targeting two metabolic genes, ATP citrate lyase (ACLY) and oxoglutarate dehydrogenase (OGDH), in HCC cells. Using valproic acid (VPA) and bempedoic acid (BA) as pharmacological inhibitors of OGDH and ACLY, respectively, we observed a strong synergistic effect in inhibiting the proliferation of HCC cell lines (Hep3B and Huh7), compared to using these drugs individually. Importantly, this combination treatment exhibited little increased cytotoxicity in the non-cancerous liver cell line THLE-2, indicating a degree of selectivity. Our findings are consistent with previous reports implicating USP13 as a metabolic regulator of ACLY and OGDH in various cancers, suggesting that the inhibition of USP13 may prevent HCC cell proliferation primarily through its downstream effects on ACLY and OGDH. By directly co-targeting ACLY and OGDH, our approach may offer a more precise and safer alternative to USP13 inhibition. Additionally, while both VPA and BA have been individually associated with beneficial effects in liver disease, their combined application in the context of HCC has not been previously investigated. Limitations include the reliance on cell line models, highlighting the need for validation in more physiologically relevant systems such as human organoids and animal models. Overall, this study provides a compelling rationale for further investigation into ACLY and OGDH as a synthetic lethal pair and the therapeutic potential of the VPA-BA combination treatment in HCC.
Insights
Targeting ATP citrate lyase (ACLY) and oxoglutarate dehydrogenase (OGDH) with valproic acid and bempedoic acid shows promise for treating liver cancer. This combination therapy selectively inhibits hepatocellular carcinoma cell growth with minimal toxicity to normal cells.
Area of Science:
- Oncology
- Metabolic pathways
- Drug discovery
Background:
- Hepatocellular carcinoma (HCC) is a major global cancer burden with limited treatment options.
- There is a critical need for novel, targeted therapies to improve HCC patient outcomes.
- Metabolic reprogramming is a hallmark of cancer, offering potential therapeutic targets.
Purpose of the Study:
- To investigate the synthetic lethality of co-targeting ATP citrate lyase (ACLY) and oxoglutarate dehydrogenase (OGDH) in HCC.
- To evaluate the efficacy and selectivity of pharmacological inhibition of ACLY and OGDH using bempedoic acid (BA) and valproic acid (VPA), respectively.
- To explore a novel therapeutic strategy for HCC by directly targeting key metabolic enzymes.
Main Methods:
- Utilized cell culture models of HCC (Hep3B, Huh7) and a non-cancerous liver cell line (THLE-2).
- Administered pharmacological inhibitors: bempedoic acid (BA) for ACLY and valproic acid (VPA) for OGDH.
- Assessed the synergistic effects on cell proliferation and cytotoxicity.
Main Results:
- The combination of VPA and BA demonstrated a strong synergistic effect in inhibiting HCC cell proliferation.
- This combined treatment showed significantly reduced cytotoxicity in normal liver cells compared to individual drugs.
- Findings support the hypothesis that targeting ACLY and OGDH exploits a synthetic lethal vulnerability in HCC.
Conclusions:
- Directly co-targeting ACLY and OGDH with VPA and BA presents a promising, selective therapeutic strategy for HCC.
- This approach may offer advantages over targeting upstream regulators like USP13.
- Further validation in preclinical models is warranted to translate these findings into clinical applications.
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