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CANCER STEM CELLS AND
ONCOLOGY RESEARCH
11
th
International Conference on
Journal of Medical Oncology and Therapeutics
|
Volume 3
Isabelle Mus-Veteau et al., J Med Oncl Ther 2018, Volume 3
TARGETING THE MULTIDRUG
TRANSPORTER PATCHED
POTENTIATES CHEMOTHERAPY
EFFICIENCY
IN VITRO
AND
IN VIVO
Isabelle Mus-Veteau
1,4
, Anida Hasanovic
1,4
, Carmen
Ruggiero
1,4
, Sara Jung
2
, Ida Rapa
3
, Marco Volante
3
,
Constanze Hantel
2
and
Enzo Lalli
1,4
1
Institut de Pharmacologie Moléculaire et Cellulaire, France
2
Ludwig-Maximilians-Universität, Germany
3
University of Turin at San Luigi Hospital, Italy
4
Université Côte d’Azur, France
O
ne of the crucial challenges in the clinical management of cancer is the
resistance to chemotherapeutics. We recently demonstrated that the
Hedgehog receptor Patched, which is overexpressed in many recurrent
and metastatic cancers, is a multidrug transporter for chemotherapeutic
agents such as doxorubicin. The present study provides evidences that
Patched is expressed in adrenocortical carcinoma (ACC) patients, and is
a major player of the doxorubicin efflux and the doxorubicin resistance
in the human ACC cell line H295R. We discovered a drug-like molecule
which inhibits the doxorubicin efflux activity of Patched, enhances the
cytotoxic, pro-apoptotic, antiproliferative and anticlonogenic effects of
doxorubicin on ACC cells which endogenously overexpress Patched, and
thereby mitigates the resistance of these cancer cells to doxorubicin.
Moreover, we report that in mice the combination of this molecule with
doxorubicin prevents the development of xenografted ACC tumors
more efficiently than doxorubicin alone by enhancing the accumulation
of doxorubicin specifically in tumors without obvious undesirable side
effect. Our results suggest that the use of an inhibitor of Patched drug
efflux in combination with doxorubicin could be a promising therapeutic
option for adrenocortical carcinoma, and most likely also for other
Patched-expressing cancers.
Isabelle Mus-Veteau is currently working at the
Institut de Pharmacologie Moléculaire et Cel-
lulaire, Sophia Antipolis, Université Côte d’Azur,
France
mus-veteau@ipmc.cnrs.frBIOGRAPHY