9 research outputs found
Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance
There is a constant need for new therapies against multidrug resistant (MDR) cancer. An attractive strategy is to develop chelators that display significant antitumor activity in multidrug resistant cancer cell lines overexpressing the drug efflux pump P-glycoprotein. In this study we used a panel of sensitive and MDR cancer cell lines to evaluate the toxicity of picolinylidene and salicylidene thiosemicarbazone, arylhydrazone, as well as picolinylidene and salicylidene hydrazino-benzothiazole derivatives. Our results confirm the collateral sensitivity of MDR cells to isatin-β-thiosemicarbazones, and identify several chelator scaffolds with a potential to overcome multidrug resistance. Analysis of structure-activity-relationships within the investigated compound library indicates that NNS and NNN donor chelators show superior toxicity as compared to ONS derivatives regardless of the resistance status of the cells. © 2016 Elsevier Masson SAS
Identification and Validation of Compounds Selectively Killing Resistant Cancer: Delineating Cell Line-Specific Effects from P-Glycoprotein-Induced Toxicity.
Despite significant progress, resistance to chemotherapy is still the main reason why cancer remains a deadly disease. An attractive strategy is to target the collateral sensitivity of otherwise multidrug resistant (MDR) cancer. In this study, our aim was to catalog various compounds that were reported to elicit increased toxicity in P-glycoprotein (Pgp)-overexpressing MDR cells. We show that the activity of most of the serendipitously identified compounds reported to target MDR cells is in fact cell-line specific, and is not influenced significantly by the function of Pgp. In contrast, novel 8-hydroxyquinoline derivatives that we identify in the National Cancer Institute (NCI) drug repository possess a robust Pgp-dependent toxic activity across diverse cell lines. Pgp expression associated with the resistance of the doxorubicin-resistant Brca1-/-;p53-/- spontaneous mouse mammary carcinoma cells could be eliminated by a single treatment with NSC57969, suggesting that MDR-selective compounds can effectively revert the MDR phenotype of cells expressing Pgp at clinically relevant levels. The discovery of new MDR-selective compounds shows the potential of this emerging technology and highlights the 8-hydroxyquinoline scaffold as a promising starting point for the development of compounds targeting the Achilles heel of drug-resistant cancer. Mol Cancer Ther; 16(1); 45-56. (c)2016 AACR
Comparative solution equilibrium studies of antitumor ruthenium(η6-p-cymene) and rhodium(η5-C5Me5) complexes of 8-hydroxyquinolines
Complex formation processes of [
Ru(η
6
-
p
-
cymene)
(H
2
O)
3
]
+
and
[
Rh(
η
5
-
C
5
Me
5
)(H
2
O)
3
]
+
organometallic
cations
with
8
-
hydroxyquinoline
(HQ) ligands were studied in aqueous solution by the combined use of
1
H NMR spectroscopy, UV
-
visible spectrophotometry and pH
-
potentiometry. Solution stability, chloride ion affinity and lipophilicity of the
complexes
were characterized together with the in vitro cytotoxicity against a pair of cancer cell lines, responsive and resistant to
classic chemotherapy.
The solid phase structure of the [Rh(
η
5
-
C
5
Me
5
)(
8
-
quinolinolato
)(Cl)] complex was characterized by
s
ingle
-
crystal X
-
ray diffraction analysis.
In addition to the unsubstituted HQ its 7
-
(1
-
piperidinylmethyl) (PHQ) and 5
-
sulfonate (
HQS) derivatives were involved. PHQ has a
significant preference for targeting
multidrug resistant cancer cell
lines
, while HQS
served as a water soluble model compound. The
equilibrium studies revealed the formation of mono
[M(L)(H
2
O)]
complexes
with prominently high solution stability, which predominate at physiological pH even in the
micromolar concentration range
, and f
ormation of mixed hydroxido [M(L)(OH)] complexes
was
characterized by relatively
high p
K
a
values (8.5
–
10.3). In comparison
to the Rh(η
5
-
C
5
Me
5
) species
the complex
ation
process with
Ru(η
6
-
p
-
cymene)
is
much
slower, and both the p
K
a
values and the H
2
O/Cl
−
co
-
ligand exchange constants are lower by
1
-
1.5 orders of
magnitude.
The stability order obtained for these organometallic complexes is as follows: HQS > HQ > PHQ. Cytotoxicity of
the ligands and their
Ru(η
6
-
p
-
cymene) and Rh(η
5
-
C
5
Me
5
) complexes was
investigated against
MES
-
SA (human uterine
sarcoma) cell line and its
multidrug resistant
counterpart (MES
-
SA/Dx5). HQ and its complexes show similar cytotoxicity in
both cell lines. In contrast, PHQ and
its Rh(η
5
-
C
5
Me
5
)
complex are more potent against MES
-
SA/Dx5 cells, while
this
selectivity could not be observed
for
the
Ru(η
6
-
p
-
cymene) complex
Unshielding Multidrug Resistant Cancer through Selective Iron Depletion of P-Glycoprotein–Expressing Cells
Clinical evidence shows that following initial response to treatment, drug-resistant cancer cells frequently evolve and, eventually, most tumors become resistant to all available therapies. We compiled a focused library consisting of >500 commercially available or newly synthetized 8-hydroxyquinoline (8OHQ) derivatives whose toxicity is paradoxically increased rather than decreased by the activity of P-glycoprotein (Pgp), a transporter conferring multidrug resistance (MDR). Here, we deciphered the mechanism of action of NSC297366 that shows exceptionally strong Pgp-potentiated toxicity. Treatment of cells with NSC297366 resulted in changes associated with the activity of potent anticancer iron chelators. Strikingly, iron depletion was more pronounced in MDR cells due to the Pgp-mediated efflux of NSC297366-iron complexes. Our results indicate that iron homeostasis can be targeted by MDR-selective compounds for the selective elimination of multidrug resistant cancer cells, setting the stage for a therapeutic approach to fight transporter-mediated drug resistance. SIGNIFICANCE: Modulation of the MDR phenotype has the potential to increase the efficacy of anticancer therapies. These findings show that the MDR transporter is a "double-edged sword" that can be turned against resistant cancer