Breast cancer is now the most frequently diagnosed cancer and leading cause of cancer death in women worldwide. Metastatic disease remains the underlying cause of death in the majority of breast cancer patients who succumb to their disease. Understanding the molecular and cellular mechanisms of motility an invasion and their inhibition is a crucial step in developing new therapies.
Met, a tyrosine kinase receptor and its ligand, Hepatocyte growth factor (HGF) /scatter factor (SF), induce specific signal transduction and metabolic pathways in tumor cells, leading to cell motility. Met FDA-approved inhibitors are effective for therapy of patients overexpressing Met protein; however, cancer cells acquire resistance to the therapy. The anthracycline chemotherapy family is effective against a wide variety of cancer types; however, cancer cells acquire resistance to these drugs. Moreover, these drugs have severe side effects such as cardiotoxicity that limits their use.
Using multimodal microscopic molecular imaging, we have recently studied the effect of Met inhibitors and novel metabolic activity of Idarubicin (IDR) and Aloe emodin glycoside-1 (AEG1) anthracyclines as target for anti-metastatic breast cancer therapy.
Colocalization analysis demonstrate that IDR/AEG1 accumulate in the lysosome. We hypothesize that IDR/AEG1 treatment induces lysosomal membrane permeabilization (LMP); Lysosome enzymes in the cytosol, damages the cells organelles including the mitochondria, which leads to mitochondria membrane depolarization and ATP depletion. Our results demonstrate that IDR/AEG1 treatment gradually reduces the mitochondria membrane potential. The effect of IDR/AEG1 is immediate (60 min.). IDR/AEG1 induce 60% reduction in membrane potential and in ATP levels in time and dose dependent manner. DOX did not decrease ATP levels. The kinetics of IDR/AEG1 induced ATP depletion correlated closely with cell viability and membrane depolarization.
Using our newly developed single cell multi parameters morpho-kinetic analysis we study how treatment with combined anti-Met and IDR/AEG1 affect motility.
Our results demonstrate that Met inhibition reduces the signaling and the metabolism required for motility. Advanced analysis of the morpho-kinetic profile, showed that human BC cell lines that express a high level of the Met receptor have decreased kinetics upon combined Met inhibition and IDR treatment. Human BC cell lines that express a low level of the Met receptor; have reduced motility when untreated and upon combined Met inhibition and IDR treatment are unchanged. These results indicates that anti-Met treatment efficacy is dependent on initial Met activation levels, high Met cells show a greater response to combined anti-Met and IDR treatment.
We demonstrate that confocal based multimodal molecular imaging is a powerful tool in understanding molecular and metabolic activity and personalizing biological therapy and chemotherapy. Using these tools, we demonstrate that Met inhibitors in combination with novel anti-metabolic activity of anthracyclines (IDR/AEG1) can serve as novel anti-metastatic therapy.
