Download Conclusions: Introduction Results

Induction of mitochondrial dysfunction as a strategy for targeting tumor
cells in hypoxic microenvironment
Xiaonan Zhang1#, Mårten Fryknäs2#, Rolf Larsson2* and Stig Linder1*
1 Department
of Oncology-Pathology, Karolinska Institute, S-171 76 Stockholm, Sweden;
2 Department of Medical Sciences, Division of Clinical Pharmacology, University Hospital, Uppsala University, S-751 85 Uppsala, Sweden
Results
Conclusions:
1.
2.
3.
4.
VLX600 kills both proliferating and quiescent
tumor cells by impairing ETC and shifting
metabolism.
VLX600 potency can be enhanced by
autophagy inhibitors.
Targeting Mitochondria respiration is a
promising strategy for solid tumor treatment
3D spheroids is an intermediate complexity
between in vivo tumors and in vitro monolayer
cultures in the drug screening.
VLX600 forms complexes
1. VLX600 impairing ETC and causing
mitochondria dysfunction analyzed by Seahorse. with ferrous and ferric
iron. Iron chloride totally
abrogates its cytotoxic effect
abovious cell death after 48h
and (non-malignant) human
epithelial hTERT-RPE1 cell
growth arrest (right).
A: Compounds B: oligomycin C: FCCP D: Rotenone and Antimycin
Respiration(up left) and
ECT (up right) impaired
after 4h VLX600.
Spheroids by EM show
swollen Mito. (down).
Introduction
1.3D spheroids is a proper model to connect in
vivo tumors and in vitro monolayer cultures in
drug screening
3.VLX600 is an iron chelator.
2. VLX600 is toxic to proliferating and quiescent
tumor cells without effect normal tissue cells
Spheroids contain populations
of hypoxic (PIMO staining) and
non-proliferating cells(markers
of Ki67 and p27). Cells in
core BIPpositive associated
with apoptosis resistance.
4. VLX 600 reduce tumor volume at low does in
vivo and autophagy inhibitor(CQ) enhances
VLX600 potency.
Central necrotic areas (“N”)
after 72h (left)
2. VLX600 discovered by spheroids screening
A dose of 0.5 mg/kg still has anti-tumor effects(up left).
The structure of VLX600
(ChemBridge 5625138),
most active of ~10,000
Compounds screened.
Karolinska Institutet
Xiaonan Zhang
PHD student, Oncology-Pathology
CCK, R8:00
17176
Contact:
E-mail: [email protected]
Tele: 0760235812