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Published on: January 3, 2012
Sensitivity of cancer cells to truncated diphtheria toxin
Yi Zhang1, Wendy Schulte, Desmond Pink
1Departments of Biochemistry and Molecular Biology and Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
Background:
Diphtheria toxin (DT) has been utilized as a prospective anti-cancer agent for the targeted delivery of cytotoxic therapy to otherwise untreatable neoplasia. DT is an extremely potent toxin for which the entry of a single molecule into a cell can be lethal. DT has been targeted to cancer cells by deleting the cell receptor-binding domain and combining the remaining catalytic portion with targeting proteins that selectively bind to the surface of cancer cells. It has been assumed that "receptorless" DT cannot bind to and kill cells. In the present study, we report that "receptorless" recombinant DT385 is in fact cytotoxic to a variety of cancer cell lines.
Methods:
In vitro cytotoxicity of DT385 was measured by cell proliferation, cell staining and apoptosis assays. For in vivo studies, the chick chorioallantoic membrane (CAM) system was used to evaluate the effect of DT385 on angiogenesis. The CAM and mouse model system was used to evaluate the effect of DT385 on HEp3 and Lewis lung carcinoma (LLC) tumor growth, respectively.
Results:
Of 18 human cancer cell lines tested, 15 were affected by DT385 with IC(50) ranging from 0.12-2.8 microM. Furthermore, high concentrations of DT385 failed to affect growth arrested cells. The cellular toxicity of DT385 was due to the inhibition of protein synthesis and induction of apoptosis. In vivo, DT385 diminished angiogenesis and decreased tumor growth in the CAM system, and inhibited the subcutaneous growth of LLC tumors in mice.
Conclusion:
DT385 possesses anti-angiogenic and anti-tumor activity and may have potential as a therapeutic agent.
Insights
Recombinant diphtheria toxin 385 (DT385), even without a receptor-binding domain, effectively kills various cancer cells by inhibiting protein synthesis and inducing apoptosis. This "receptorless" toxin also demonstrated anti-angiogenic and anti-tumor effects in vivo.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Diphtheria toxin (DT) is a potent cytotoxic agent explored for targeted cancer therapy.
- Modified DT, lacking its receptor-binding domain, was presumed non-toxic.
- This study investigates the cytotoxic potential of a modified DT, termed DT385.
Purpose of the Study:
- To evaluate the cytotoxic effects of
- receptorless
- recombinant diphtheria toxin 385 (DT385) on various cancer cell lines.
- To assess the in vivo anti-tumor and anti-angiogenic activities of DT385.
Main Methods:
- In vitro cytotoxicity assessed via cell proliferation, staining, and apoptosis assays.
- In vivo studies utilized the chick chorioallantoic membrane (CAM) model for angiogenesis.
- Tumor growth inhibition evaluated in CAM and mouse models (HEp3 and Lewis lung carcinoma).
Main Results:
- DT385 exhibited cytotoxicity against 15 out of 18 tested human cancer cell lines (IC50: 0.12-2.8 microM).
- Toxicity mechanism involves protein synthesis inhibition and apoptosis induction.
- DT385 demonstrated anti-angiogenic effects and inhibited tumor growth in vivo models.
Conclusions:
- DT385 displays significant anti-angiogenic and anti-tumor properties.
- The modified diphtheria toxin (DT385) shows therapeutic potential for cancer treatment.
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