Steroidal cardiac Na+/K+ ATPase inhibitors exhibit strong anti-cancer potential in vitro and in prostate and lung cancer xenografts in vivo.
Sodium potassium pump (Na(+)/K(+)ATPase) is a validated pharmacological target for the treatment of congestive heart failure. Recent data with inotropic drugs such as digoxin & digitoxin (digitalis) suggest a potent anti-cancer action of these drugs and promote Na(+)/K(+)ATPase as a novel therapeutic target in cancer. However, digitalis have narrow therapeutic indices, are pro-arrhythmic and are considered non-developable drugs by the pharmaceutical industry. On the contrary, a series of recently-developed steroidal inhibitors showed better pharmacological properties and clinical activities in cardiac patients. Their anti-cancer activity however, remained unknown. In this study, we synthesized seventeen steroidal cardiac inhibitors and explored for the first time their anti-cancer activity in vitro and in vivo. Our results indicate potent anti-cancer actions of steroidal cardiac inhibitors in multiple cell lines from different tumor panels including multi-drug resistant cells. Furthermore, the most potent compound identified in our studies, the 3-[(R)-3- pyrrolidinyl]oxime derivative 3, showed outstanding potencies (as measured by GI50, TGI and LC50 values) in most cells in vitro, was selectively cytotoxic in cancer versus normal cells showing a therapeutic index of 31.7 and exhibited significant tumor growth inhibition in prostate and lung xenografts in vivo. Collectively, our results suggest that previously described cardiac Na(+)/K(+)ATPase inhibitors have potent anti-cancer actions and may thus constitute strong re-purposing candidates for further cancer drug development.
Konstantinos
K
Dimas
Natalia
N
Papadopoulou
Constantinos
C
Baskakis
Kyriakos C
KC
Prousis
Michail
M
Tsakos
Saad
S
Alkahtani
Sabina
S
Honisch
Florian
F
Lang
Theodora
T
Calogeropoulou
Konstantinos
K
Alevizopoulos
Department of Biochemistry, University of Crete Medical School, GR-71110, Heraklion, Greece. cstourn@med.uoc.gr.
Christos
C
Stournaras
D000736:Androstenes / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D005260:Female; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D016513:Mice, SCID; D009206:Myocardium / Q000201:enzymology*; D009368:Neoplasm Transplantation; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013256:Steroids / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
C000593419:3-(pyrrolidin-3-yloxyimino)-6-methyleneandrostane-17-one; D000736:Androstenes; D000970:Antineoplastic Agents; D010091:Oximes; D011759:Pyrrolidines; D013256:Steroids; D000254:Sodium-Potassium-Exchanging ATPase