Common chemotherapeutic agents modulate fatty acid distribution in human hepatocellular carcinoma and colorectal cancer cells

Abstract

Introduction: Cancer cells are critically correlated with lipid molecules, particularly fatty acids, as structural blocks for membrane building, energy sources, and related signaling molecules. Therefore, cancer progression is in direct correlation with fatty acid metabolism. The aim of this study was to investigate the potential effects of common chemotherapeutic agents on the lipid metabolism of hepatocellular carcinoma (HCC) and colorectal cancer (CRC) cells, with a focus on alterations in cellular fatty acid contents. Methods: Human HepG2 and SW480 cell lines as HCC and CRC cells were respectively cultured in RPMI-1640 medium supplemented with non-toxic doses of 5-fluorouracil and doxorubicin for 72 hours. Oil Red O dye was used to estimate intracellular lipid vacuole intensity. Fatty acid analysis of isolated membrane phospholipids and cytoplasmic triglycerides (TG) was performed by gas-liquid chromatography (GLC) technique. Results: Oil red O staining represented significantly higher lipid accumulation and density in cancer cells after exposure to the chemotherapeutic agents as compared to non-treated control cells. Doxorubicin and 5-fluorouracil treatment promoted the channeling of saturated fatty acids (SFAs) from phospholipids to triglyceride pool in both HepG2 (+5.91% and +8.50%, P < 0.05, respectively) and SW480 (+37.41% and +5.73%, P < 0.05, respectively) cell lines. However, total polyunsaturated fatty acid content was inversely shifted from TG to phospholipid fraction after doxorubicin and 5-fluorouracil incubation of HepG2 (+58.89% and +29.13%, P < 0.05, respectively) and SW480 (+19.20% and +14.65%, P < 0.05, respectively) cells. Conclusion: Our data showed that common chemotherapeutic agents of HCC and CRC can induce significant changes in cellular lipid accumulation and distribution of fatty acids through producing highly saturated and unsaturated lipid droplets and membrane lipids, respectively. These metabolic side effects may be associated with gastrointestinal cancers treatment failure.

Decreased Efficacy of Doxorubicin Corresponds With Modifications in Lipid Metabolism Markers and Fatty Acid Profiles in Breast Tumors From Obese vs. Lean Mice

“…For example, doxorubicin and 5-fluorouracil treatment significantly increased the number of lipid droplets within HepG2 cancer cells. They also reported a significant increase in SFAs (PA) and PUFAs and a significant decrease in MUFAs (OA and PTA) following chemotherapy treatments in the phospholipid fractions of the membranes of cancer cells (93).…”

“…However, the authors explained that it is still unknown whether the suppression of adipose tissue lipid storage capacity induced by chemotherapy is a result of decreased HSL expression, or due to mitochondrial dysfunction induced by the chemotherapy (92). Mehdizadeh et al (93) showed that doxorubicin and 5-fluorouracil have FIGURE 13 | Summary of findings. DIO selectively supresses de novo FA synthesis and lipolysis in mammary adipose tissue, but increased lipogenesis and lipolysis in tumor tissue.…”

Dropping in on lipid droplets: insights into cellular stress and cancer

“…Treatment of N-myc proto-oncogene protein-amplified neuroblastoma cells with 10058-F4, an inhibitor of c-MYC/Max protein, a member of the basic helix–loop–helix leucine zipper family of transcription factors, triggers the accumulation of intracellular LDs as an outcome of mitochondrial dysfunction. The chemotherapeutic drugs doxorubicin and 5-fluorouracil (5-FU) in human colon carcinoma cells induce the accumulation of LDs as a result of up-regulated TG biosynthesis [ 192 , 202 ]. Hence, this points to a potential role for LDs as part of a general stress response to different classes of chemotherapeutic treatments.…”

Innovation for hepatotoxicity in vitro research models: A review

“…Various media supplements such as amino acids, hormones, growth factors, and other co-factors are important in primary culture. Dulbecco's modified Eagle's medium (Cho et al, 2015;Nemoto, Sakurai, Tazawa, & Ishikawa, 1989;Nikoozad, Ghorbanian, & Rezaei, 2014;Wu et al, 2015;Zhang et al, 2014), Williams' E (Shibany, Totemeyer, Pratt, & Paine, 2016;Shri, Agrawal, Rani, Singh, & Onteru, 2017;Tomizawa et al, 2016b), Waymouth's MB (Rodriguez-Enriquez, Kai, Maldonado, Currin, & Lemasters, 2009), Ham's F12 (Rattanasinganchan et al, 2006;Sripa et al, 2005), RPMI 1640 (Horai et al, 2014;Khosravi, Shokri, & Eshghi, 2017;Mehdizadeh et al, 2017) and Leibovitz's 15 (L-15) (Anene, Rosenberg, Kleiner, Cornish, & Halushka, 2016;Mitaka, Sattler, & Pitot, 1991) are all available media formulations. Highly enriched media, which contain amino acid concentrations that are 5-10 times higher than most standard media, are superior for the maintenance of cell survival, preserving cellular protein levels and liver-specific functions (Gebhardt et al, 2003;Swift, Pfeifer, & Brouwer, 2010).…”