Change search
ReferencesLink to record
Permanent link

Direct link
alpha-Toxin of Staphylococcus aureus overcomes acquired cisplatin-resistance in malignant mesothelioma cells.
Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
Umeå University, Faculty of Medicine, Odontology. (Aa-gruppen)
Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
2008 (English)In: Cancer Letters, ISSN 0304-3835, Vol. 265, no 1, 67-75 p.Article in journal (Refereed) Published
Abstract [en]

alpha-Toxin (alpha-hemolysin) of Staphylococcus aureus is a pore-forming bacterial toxin which after caveolin-1-dependent assembly induces apoptosis in eukaryotic cells. We investigated if a sub-toxic concentration of staphylococcal alpha-toxin could enhance cisplatin-induced apoptosis and overcome acquired cisplatin-resistance in cultured malignant pleural mesothelioma (MPM) cells. MPM cells (P31wt) and a cisplatin-resistant sub-line (P31res) was incubated with alpha-toxin and/or cisplatin followed by determination of cell viability, apoptosis, and signaling pathways. P31res cells were more sensitive to alpha-toxin than P31 wt cells due to induction of apoptosis. A low-toxic concentration of alpha-toxin re-sensitized cisplatin P31res cytotoxicity by apoptosis-induced through the mitochondrial pathway without detectable activation of common up-stream apoptosis signaling proteins. The toxin/drug combination should be tested for cisplatin-resistant mesothelioma treatment.

Place, publisher, year, edition, pages
2008. Vol. 265, no 1, 67-75 p.
URN: urn:nbn:se:umu:diva-22902DOI: 10.1016/j.canlet.2008.02.007PubMedID: 18362050OAI: diva2:218472
Available from: 2009-05-19 Created: 2009-05-19 Last updated: 2010-01-21
In thesis
1. Bacterial toxins for cancer treatment
Open this publication in new window or tab >>Bacterial toxins for cancer treatment
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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 apoptosis signalling proteins.

VT‐1 was highly cytotoxic and induced apoptosis in globotriosylceramide (Gb3) ‐expressing glioma, breast cancer and non‐small‐cell lung cancer (NSCLC) cells but was not cytotoxic to non‐Gb3‐expressing cells. PPMP, an inhibitor of glucosylceramide synthesis which makes exposed cells unable to synthesize Gb3 rendered Gb3‐expressing cells resistant to VT‐1. MPM cells with acquired‐cisplatin resistance expressed Gb3 in contrast to the absent of expression in the less resistant parental cell line. Gb3, could however be up‐regulated by cisplatin in Gb3‐negative MPM‐cells. Presence of a low‐toxic concentration of VT‐1 potentiated cisplatin‐induced cytotoxicity and apoptosis in the cisplatin‐resistance MPM cell line. VT‐1 was a potent inducer of apoptosis, probably via stress‐induced Mitogen‐activated protein kinase (MAPK)‐signaling involving c‐Jun N‐terminal kinase (JNK) and p38, leading to disruption of the mitochondrial membrane integrety, activation of caspase‐9 and ‐3, and ultimately DNA fragmentation and cell death. Gb3 expression was demonstrated in clinical specimens of glioblastoma and breast cancer making these tumor types interesting for further VT‐1 studies.

We conclude that bacterial toxins may be used to induce apoptosis in several types of cancer cells. Low concentrations of verotoxin‐1 and α‐toxin may potentially be used to overcome acquired cisplatin‐resistance in cancer patients.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap, 2008. 47 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1178
Alpha‐toxin, AC‐toxin, mesothelioma, lung cancer, glioma, breast cancer, caspases, MAP-Kinase, verotoxin‐1, cisplatin, apoptosis, Gb3, drug resistance
National Category
Other Clinical Medicine
urn:nbn:se:umu:diva-1637 (URN)978-91-7264-566-0 (ISBN)
Public defence
2008-05-23, Sal D, 1D, 9 trappor, Norrlands universitetssjukhus, Umeå, 13:00 (English)
Available from: 2008-05-05 Created: 2008-05-05 Last updated: 2010-01-21Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Johansson, AndersBehnam-Motlagh, Parviz
By organisation
Clinical chemistryOdontology
In the same journal
Cancer Letters

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 62 hits
ReferencesLink to record
Permanent link

Direct link