Bacterial toxins for cancer treatment

Even though anti‐cancer chemotherapy has been continuously improved during the last decades. problems with adverse effects and drug resistance still constitutes a considerable obstacle and sets a demand for new effective treatment options. Tissue homeostasis in multi‐cellular organisms is maintained through intrinsic cell death, apoptosis, which removes unwanted or damaged cells. Disrupted apoptosis is an important factor in tumorgenesis and drug resistance, therefore induction or restoration of apoptotic pathways is also important for the treatment of cancer. Several naturally occurring bacterial toxins have the ability to induce apoptosis and could thus be candidates to complement or improve the therapeutic effect of other anticancer drugs.The bacterial toxins, adenylate cyclase (AC) toxin from Bordetella pertussis, α‐toxin from Staphylococcus aureus and verotoxin‐1 (VT‐1) from Escherichia coli were investigated for their ability to induce apoptosis in different tumor cell lines. Toxin induction of cell death was investigated by cell viability assays, end‐stage apoptosis induction by DNA‐fregmentation (TUNEL) assay. Toxin receptor expression and signal transduction pathways to apoptosis were investigated by flow cytometry, caspase enzyme activity assays and western blot. Immunohistochemistry was used for identification of toxin receptor expression in tumor tissue samples.AC‐toxin was cytotoxic and induced apoptosis in cultured malignant plural mesothelioma (MPM) and small‐cell lung cancer (SCLC) cells. Low‐toxic concentrations of AC‐toxin enhanced cisplatin cytotoxicity and apoptosis in both cell lines.MPM‐cells with acquired cisplatin resistance were more sensitive to α‐toxin than the less resistant parental MPM cell line. A low‐toxic concentration of α‐toxin re‐sensitized resistant MPM cells to cisplatin cytotoxicity by apoptosis induced through the mitochondrial pathway without detectable activation of common up‐stream…


Bacterial  Toxins
AC‐toxin of  Bordetella pertussis
α‐toxin of  Staphylococcus aureus
VT‐1 of Escherichia coli
Caspases,  Bcl ‐2 and Mitogen‐activated Protein Kinases
Cancer and Current Treatment
Materials and Methods
Cell  Lines and  Inducers of Apoptosis
Cytotoxicity Assays
Apoptosis – Detection and Quantification
Apoptosis – Signaling Pathways
Detection and Manipulation of  Toxin Receptors
Results and Discussion
Adenylate Cyclase‐toxin  (I)
AC‐toxin  Increases the Cytotoxic Effect of Cisplatin
AC‐toxin‐enhanced Cisplatin Cytotoxicity  Involves  Increased
Alpha‐toxin (II)
α‐toxin  Induces Apoptosis  in MPM and NSCLC Cells
α‐toxin Enhances Cisplatin‐induced Apoptosis
Signal  Transduction  in α‐toxin‐enhanced Cisplatin‐ induced Apoptosis
Verotoxin‐1 (III ‐V)
VT‐1  Induces Apoptosis  in Cells Expressing Gb3
Cisplatin Up‐regulates Gb3 expressio
Presence of  VT‐1 Sensitizes Cells to Cisplatin Treatment
Signal  Transduction of  VT‐1‐ induced Apoptosis
Tumor‐expression of  Gb3
General  Discussion and Conclusions

Author: Johansson, David

Source: Umea University

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