TY - JOUR
T1 - Multitargeting Prodrugs that Release Oxaliplatin, Doxorubicin and Gemcitabine are Potent Inhibitors of Tumor Growth and Effective Inducers of Immunogenic Cell Death
AU - Sarkar, Amrita
AU - Novohradsky, Vojtech
AU - Maji, Moumita
AU - Babu, Tomer
AU - Markova, Lenka
AU - Kostrhunova, Hana
AU - Kasparkova, Jana
AU - Gandin, Valentina
AU - Brabec, Viktor
AU - Gibson, Dan
N1 - Publisher Copyright:
© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.
PY - 2023/10/16
Y1 - 2023/10/16
N2 - A multitargeting prodrug (2) that releases gemcitabine, oxaliplatin, and doxorubicin in their active form in cancer cells is a potent cytotoxic agent with nM IC50s; it is highly selective to cancer cells with mean selectivity indices to human (136) and murine (320) cancer cells. It effectively induces release of DAMPs (CALR, ATP & HMGB1) in CT26 cells facilitating more efficient phagocytosis by J774 macrophages than the FDA drugs or their co-administration. The viability of CT26 cells co-cultured with J774 macrophages and treated with 2 was reduced by 32 % compared to the non-treated cells, suggesting a synergistic antiproliferative effect between the chemical and immune reactions. 2 inhibited in vivo tumor growth in two murine models (LLC and CT26) better than the FDA drugs or their co-administration with significantly lower body weight loss. Mice inoculated with CT26 cells treated with 2 showed slightly better tumor free survival than doxorubicin.
AB - A multitargeting prodrug (2) that releases gemcitabine, oxaliplatin, and doxorubicin in their active form in cancer cells is a potent cytotoxic agent with nM IC50s; it is highly selective to cancer cells with mean selectivity indices to human (136) and murine (320) cancer cells. It effectively induces release of DAMPs (CALR, ATP & HMGB1) in CT26 cells facilitating more efficient phagocytosis by J774 macrophages than the FDA drugs or their co-administration. The viability of CT26 cells co-cultured with J774 macrophages and treated with 2 was reduced by 32 % compared to the non-treated cells, suggesting a synergistic antiproliferative effect between the chemical and immune reactions. 2 inhibited in vivo tumor growth in two murine models (LLC and CT26) better than the FDA drugs or their co-administration with significantly lower body weight loss. Mice inoculated with CT26 cells treated with 2 showed slightly better tumor free survival than doxorubicin.
KW - Doxorubicin
KW - Gemcitabine
KW - Immunogenic Cell Death
KW - Multi-Targeting Prodrugs
KW - Oxaliplatin
UR - http://www.scopus.com/inward/record.url?scp=85170356579&partnerID=8YFLogxK
U2 - 10.1002/anie.202310774
DO - 10.1002/anie.202310774
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C2 - 37646232
AN - SCOPUS:85170356579
SN - 1433-7851
VL - 62
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 42
M1 - e202310774
ER -