Cell Lineage Dependent Apoptotic and Immunomodulatory Signaling Induced By Parthenin Analog P19: An Insight to Molecular Mechanism and Therapeutic Implications

Abstract

\n Leukemia is one of the deadliest types of cancer. Specifically, acute lymphoid leukemia (ALL) has been considered as one of the most lethal types of cancer. Due to the rapid progress in the various cancer cases and the accumulation of resistances in the cancer cells, the discovery of the new lead molecules with more effective anticancer properties are required. There is a growing interest in using herbal products/analogs as multi-component agents (as anticancer agents and immunomodulators) for cancer treatment. In the present investigation, an attempt has been made to explore the anticancer and immunomodulatory activity of P19 in ALL. P19 was reported to demonstrate the anticancer activity by activation of apoptotic signaling events through robust NO formation in human leukemia HL-60 cells. Contrary to this observation, P19 mediated apoptosis in Raji cells was independent of NO and ROS induction. The mechanism of P19 was observed to be cancer cell lineage dependent. Further, P19 demonstrated very effective anticancer properties against ALL (IC50 3µM). Molecular investigations revealed that P19 induced mitochondrion mediated apoptosis by Bax localization to mitochondria and enhanced cytosolic calcium in the cytoplasm. Further activation of the caspase 3, caspase 8 and PARP cleavage suggested the involvement of the caspase-mediated apoptosis. Anti-proliferative activity revealed the telomerase inhibition and cell cycle arrest in G0/G1 phase after P19 treatment. Immunomodulatory effects of the P19 revealed the enhanced INFɣ and NO production in Jurkat and THP cells. Owing to its antiproliferative and immunomodulatory potential against leukemia cells P19 can further be explored as an effective therapeutics against leukemia.