Targeting claudin-overexpressing thyroid and lung cancer by modified Clostridium perfringens enterotoxin.
Mol Oncol
; 14(2): 261-276, 2020 02.
Article
in En
| MEDLINE
| ID: mdl-31825142
ABSTRACT
Clostridium perfringens enterotoxin (CPE) can be used to eliminate carcinoma cells that overexpress on their cell surface CPE receptors - a subset of claudins (e.g., Cldn3 and Cldn4). However, CPE cannot target tumors expressing solely CPE-insensitive claudins (such as Cldn1 and Cldn5). To overcome this limitation, structure-guided modifications were used to generate CPE variants that can strongly bind to Cldn1, Cldn2 and/or Cldn5, while maintaining the ability to bind Cldn3 and Cldn4. This enabled (a) targeting of the most frequent endocrine malignancy, namely, Cldn1-overexpressing thyroid cancer, and (b) improved targeting of the most common cancer type worldwide, non-small-cell lung cancer (NSCLC), which is characterized by high expression of several claudins, including Cldn1 and Cldn5. Different CPE variants, including the novel mutant CPE-Mut3 (S231R/S313H), were applied on thyroid cancer (K1 cells) and NSCLC (PC-9 cells) models. In vitro, CPE-Mut3, but not CPEwt, showed Cldn1-dependent binding and cytotoxicity toward K1 cells. For PC-9 cells, CPE-Mut3 improved claudin-dependent cytotoxic targeting, when compared to CPEwt. In vivo, intratumoral injection of CPE-Mut3 in xenograft models bearing K1 or PC-9 tumors induced necrosis and reduced the growth of both tumor types. Thus, directed modification of CPE enables eradication of tumor entities that cannot be targeted by CPEwt, for instance, Cldn1-overexpressing thyroid cancer by using the novel CPE-Mut3.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Thyroid Neoplasms
/
Clostridium perfringens
/
Enterotoxins
/
Claudins
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Lung Neoplasms
/
Antineoplastic Agents
Language:
En
Journal:
Mol Oncol
Journal subject:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Year:
2020
Document type:
Article
Affiliation country: