STUDY THE INVOLVEMENT OF LYSOSOMAL CALCIUM SIGNALING IN THE ANTI-CANCER ACTIVITY OF THE LANTHANIDE PR-MPO

Abstract

WE SYNTHESIZED A CONJUGATE OF THE LANTHANIDE, PRASEODYMIUM (141PR), AND OBSERVED REMARKABLE ANTI-TUMOR ACTIVITY IN 2 MURINE XENOGRAFT MODELS (COLORECTAL AND PROSTATE CANCER), WITH MINIMAL OFF TARGET EFFECTS. IMPORTANTLY, PR-MERCAPTOPYRIDINE OXIDE (PR-MPO) ELICITED STRONG ANTI-CANCER ACTIVITY (IC50~2.5UM) AGAINST A HOST OF HUMAN CANCER CELL LINES INCLUDING CISPLATIN RESISTANT, P53-/- AND/OR BAX-/- VARIANTS. INTERESTINGLY, PR-MPO INDUCED A SIGNIFICANT INCREASE IN INTRACELLULAR CALCIUM FLUORESCENCE, MEASURED BY TIME RESOLVED LIVE IMAGING, HOWEVER, UNLIKE THAPSIGARGIN, THE INCREASE IN CALCIUM WAS NOT MEDIATED BY ER CALCIUM STORES. INSTEAD, A SIGNIFICANT INCREASE IN CALCIUM FLUORESCENCE (PUNCTA) WAS OBSERVED WITHIN MINUTES, A PATTERN DISTINCTLY DIFFERENT FROM THE DIFFUSE CYTOSOLIC INCREASE UPON DEPLETING ER CALCIUM. NOTABLY, CHELATION OF EXTRACELLULAR CALCIUM ABROGATED THE INCREASE IN INTRACELLULAR CALCIUM AS WELL AS RESCUED CELLS FROM PR-MPO-INDUCED CELL DEATH, THUS SUGGESTING THE INVOLVEM