Chemoresistance to Cancer Treatment: Benzo-α-Pyrene as Friend or Foe?

Abstract

Background: Environmental pollution such as exposure to pro-carcinogens including benzo-α-pyrene is becoming a major problem globally. Moreover, the effects of benzo-α-pyrene (BaP) on drug pharmacokinetics, pharmacodynamics, and drug resistance warrant further investigation, especially in cancer outpatient chemotherapy where exposure to environmental pollutants might occur. Method: We report here on the effects of benzo-α-pyrene on esophageal cancer cells in vitro, alone, or in combination with chemotherapeutic drugs cisplatin, 5-flurouracil, or paclitaxel. As the study endpoints, we employed expression of proteins involved in cell proliferation, drug metabolism, apoptosis, cell cycle analysis, colony formation, migration, and signaling cascades in the WHCO1 esophageal cancer cell line after 24 h of treatment. Results: Benzo-α-pyrene had no significant effect on WHCO1 cancer cell proliferation but reversed the effect of chemotherapeutic drugs by reducing drug-induced cell death and apoptosis by 30–40% compared to drug-treated cells. The three drugs significantly reduced WHCO1 cell migration by 40–50% compared to control and BaP-treated cells. Combined exposure to drugs was associated with significantly increased apoptosis and reduced colony formation. Evaluation of survival signaling cascades showed that although the MEK-ERK and Akt pathways were activated in the presence of drugs, BaP was a stronger activator of the MEK-ERK and Akt pathways than the drugs. Conclusion: The present study suggest that BaP can reverse the effects of drugs on cancer cells via the activation of survival signaling pathways and upregulation of anti-apoptotic proteins such as Bcl-2 and Bcl-xL. Our data show that BaP contribute to the development of chemoresistant cancer cells.

Cancer Stem Cell Markers in Relation to Patient Survival Outcomes: Lessons for Integrative Diagnostics and Next-Generation Anticancer Drug Development

“…Whilst current anti-cancer strategies target genetic and epigenetic changes in cancer cells, most of these have proved to be unsuccessful [3][4][5][6][7]. Detailed analyses of tumors have revealed the important role the tumor microenvironment (TME) play in tumor maintenance and therapy resistance [8][9][10][11][12][13][14].…”

Architecture of Cancer-Associated Fibroblasts in Tumor Microenvironment: Mapping Their Origins, Heterogeneity, and Role in Cancer Therapy Resistance

“…Globally, lung cancer causes the most cancer deaths, accounting for 18.4 % of cancer deaths [2]. Some the main risk factors include exposure to tobacco, smoke and asbestos [1,122,129,130]. With the exception of FAP expression, which was significantly upregulated, the expression of other CAF markers was significantly downregulated in TCGA lung adenocarcinoma samples compared to normal samples ( Figure 5).…”

“…Esophageal cancer malignancy is high and it has a poor prognosis [130,138,139]. Novel molecular targets are definitely required for durable cancer treatment.…”

Cancer-associated Fibroblasts: Origins, Heterogeneity and Functions in Tumor Microenvironment

“…Esophageal cancer malignancy is high and it has a poor prognosis [130,138,139]. Novel molecular targets are definitely required for durable cancer treatment.…”