Aluminum chloride causes 5‐fluorouracil resistance in hepatocellular carcinoma HepG2 cells

Abstract

Chemoresistance is one of the major obstacles in chemotherapy-based hepatocellular carcinoma (HCC) intervention. Aluminum (Al) is an environmental pollutant that plays a vital role in carcinogenesis, tumorigenesis, and metastasis. However, the effect of Al on chemoresistance remains unknown. 5-Fluorouracil (5-FU) is a widely used antitumor drug. Therefore, we investigated the effects of aluminum chloride (AlCl 3 ) on the chemoresistance of HepG2 cells to 5-FU and explored the underlying mechanisms of these effects. The results demonstrated that AlCl 3 pretreatment attenuated 5-FUinduced apoptosis through Erk activation and reversed 5-FU-induced cell cycle arrest by downregulating p-Chk2 Thr68 levels. In addition, AlCl 3 markedly increased the levels of proteins associated with cell migration, such as MMP-2 and MMP-9. Further investigation demonstrated that an Erk inhibitor (U0126) reversed the AlCl 3 -induced decrease in apoptosis, enhancement of cell cycle progression, promotion of cell migration, and attenuation of oxidative stress. In summary, AlCl 3 induced chemoresistance to 5-FU in HepG2 cells. The present study suggests a potential influence of AlCl 3 on 5-FU therapy. These findings may help others to understand and properly address the resistance of HCC to chemotherapeutic agents.

Interaction between environmental pollutants and cancer drug efficacy: Bisphenol A, Bisphenol A diglycidyl ether and Perfluorooctanoic acid reduce vincristine cytotoxicity in acute lymphoblastic leukemia cells

“…Consistent with other reports (An et al, 2014;Delgado & Ribeiro-Varandas, 2015;Huang et al, 2020;LaPensee et al, 2009LaPensee et al, , 2010Li et al, 2019;Merk et al, 2020;Nair et al, 2020;Ramos et al, 2019;Sonavane et al, 2018), the pollutants tested here were only able to significantly reduce the cytotoxic effects of the chemotherapy drug when exposure occurred earlier. This would indicate that pollutants need to activate evasion mechanisms before cells face cytotoxic effects.…”

NOD2 inhibits tumorigenesis and increases chemosensitivity of hepatocellular carcinoma by targeting AMPK pathway

“…Sorafenib, a tyrosine kinase inhibitor (TKI), was the FDA-approved first-line drug for advanced HCC patients 23 ; while another TKI, lenvatinib has also been approved by FDA as a new firstline treatment for HCC in August 2018. 5-FU is a widely used anti-tumor drug for multiple cancers 24 , and it is also commonly used in the clinical treatment of HCC 25 . These three types of chemotherapeutic drugs are commonly used for the HCC patients and we were interested in Fig.…”

Can Exposure to Environmental Pollutants Be Associated with Less Effective Chemotherapy in Cancer Patients?

“…Furthermore, there was also a reduction in the concentration of reactive oxygen species (ROS) and an increase in the levels of the antioxidant enzymes GPx-1 and SOD2, both also dependent on the concentration of the pollutant. Importantly, it was observed that co-treatments caused the activation of the MAPK/ERK signaling pathway and as a result of this, the progression of the cell cycle was promoted by increasing the phosphorylation of CHK2 in threonine 68, as well as cell migration increased as a result of the high levels of metalloproteases MMP-2 and MMP-9 [ 19 ]. Presumably, the antioxidant activity of AlCl 3 may also have some connection with these findings since it could mitigate ROS induced by chemotherapeutic agents to some degree [ 89 ].…”