Selective Cytotoxicity of Piperine Over Multidrug Resistance Leukemic Cells

Area of Science:

• Oncology
• Pharmacology
• Biochemistry

Background:

• Multidrug resistance (MDR) poses a significant challenge in treating chronic myeloid leukemia (CML).
• P-glycoprotein (P-gp) overexpression is a key mechanism driving MDR in CML.
• Collateral sensitivity (CS) offers a potential strategy to overcome MDR by selectively targeting resistant cells.

Purpose of the Study:

• To investigate the effect of piperine on inducing CS in CML MDR cells.
• To elucidate the mechanisms underlying piperine-induced CS, including P-gp dependence and potential involvement of PARP-1.

Main Methods:

• Cytotoxicity assays (metabolic activity, viability, cell morphology, apoptosis) were performed on K562 parental cells and K562-derived MDR cells (Lucena-1, FEPS).
• The role of P-gp in CS induction was assessed.
• The involvement of poly (ADP-ribose) polymerase-1 (PARP-1) was investigated by analyzing the 24 kDa fragment levels in MDR cells.

Main Results:

• Piperine demonstrated increased cytotoxicity towards CML MDR cells (Lucena-1, FEPS) compared to the parental K562 cells, confirming CS induction.
• CS induction was partially dependent on P-gp.
• Piperine reduced the levels of the 24 kDa PARP-1 fragment in MDR FEPS cells, suggesting a P-gp independent mechanism.

Conclusions:

• Piperine selectively induces collateral sensitivity in CML MDR cells.
• The mechanism of piperine-induced CS may involve both P-gp dependent and independent pathways, including modulation of PARP-1.
• Piperine represents a promising agent for targeting MDR in CML.