Unlocking Cancer's Fuel Source: How Fatty Acid Metabolism Could Revolutionize Myeloma Treatment

Targeting fatty acid metabolism represents a promising therapeutic approach because multiple myeloma cells, unlike normal cells, rewire their metabolic pathways to support rapid growth and division. By inhibiting key processes such as β-oxidation (the breakdown of fatty acids) and de novo fatty acid synthesis (the creation of new fatty acids), scientists aim to disrupt these altered pathways, effectively starving the cancer cells and slowing their proliferation. This approach leverages the unique metabolic vulnerabilities of myeloma cells, potentially leading to more effective and targeted treatments.

Etomoxir and orlistat are inhibitors used to disrupt fatty acid metabolism in myeloma cells. Etomoxir specifically blocks β-oxidation, preventing the breakdown of fatty acids. Orlistat inhibits de novo fatty acid synthesis, thereby stopping the creation of new fatty acids. The combined effect of these inhibitors reduces cell viability, causes cell cycle arrest in the G0/G1 phase, and reduces proliferation. Additionally, orlistat induces apoptosis (programmed cell death) and sensitizes myeloma cells to bortezomib, while etomoxir does not alter apoptosis.

Inhibiting fatty acid metabolism led to several significant changes in myeloma cell behavior. Researchers observed a reduction in cell viability, indicating that myeloma cells rely on fatty acid metabolism for survival. The inhibitors caused cell cycle arrest in the G0/G1 phase, preventing the cells from dividing. The combination of etomoxir and orlistat had an additive inhibitory effect, further reducing cell proliferation. Furthermore, orlistat induced apoptosis in myeloma cells and sensitized them to bortezomib. These inhibitory effects were associated with reduced levels of p21 protein and decreased phosphorylation of retinoblastoma protein (pRb), both key regulators of cell cycle progression.

β-oxidation (the breakdown of fatty acids) and de novo fatty acid synthesis (the creation of new fatty acids) are critical metabolic pathways that myeloma cells utilize to support their rapid growth and proliferation. Myeloma cells often upregulate these processes to meet their energy and building block demands. By targeting β-oxidation with inhibitors like etomoxir and de novo fatty acid synthesis with drugs like orlistat, researchers aim to disrupt the energy supply and building block production necessary for myeloma cell survival and division, making these pathways attractive targets for therapeutic intervention. Disrupting these processes can lead to cell cycle arrest, reduced proliferation, and apoptosis.

The observation of reduced levels of p21 protein and decreased phosphorylation of retinoblastoma protein (pRb) is significant because both p21 and pRb are key regulators of cell cycle progression. P21 is a protein that inhibits cell cycle progression, and its reduction suggests a disruption in cell cycle control. Similarly, decreased phosphorylation of pRb indicates that the retinoblastoma protein is less active, which also leads to cell cycle arrest. These changes provide mechanistic insights into how inhibiting fatty acid metabolism disrupts cell cycle progression in myeloma cells, ultimately reducing their proliferation and contributing to cell death. These findings highlight the intricate molecular pathways affected by targeting fatty acid metabolism and underscore the potential for therapeutic intervention.