Targeting poly (ADP-ribose) polymerase partially contributes to bufalin-induced cell death in multiple myeloma cells

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Multiple myeloma (MM) remains an incurable hematologic malignancy despite therapeutic advances.
• Poly(ADP-ribose) polymerase 1 (PARP1) is a potential therapeutic target in MM.
• Bufalin, a component of "Chan Su", may inhibit PARP1, but requires verification.

Purpose of the Study:

• To investigate bufalin's potential as a PARP1 inhibitor for MM therapy.
• To elucidate the mechanisms underlying bufalin's anti-MM effects.
• To evaluate bufalin's efficacy as a chemosensitizer in MM treatment.

Main Methods:

• In vitro inhibition assays and molecular docking to assess bufalin's interaction with PARP1.
• Cell proliferation assays, apoptosis analysis (morphology, Annexin-V, caspase-3), and cell cycle analysis (G2-M arrest) in MM cell lines and primary cells.
• PARP1 overexpression studies to determine its role in bufalin-induced apoptosis.
• Combination studies with standard MM chemotherapeutic agents.

Main Results:

• Bufalin demonstrated direct inhibition of PARP1 activity in vitro and reduced poly(ADP-ribosyl)ation in MM cells.
• Molecular docking confirmed bufalin's binding within the catalytic domain of PARP1.
• Bufalin significantly inhibited proliferation of MM cell lines and primary cells via apoptosis induction and G2-M cell cycle arrest.
• PARP1 overexpression partially attenuated bufalin-induced MM cell death.
• Bufalin enhanced the anti-proliferative effects of topotecan, camptothecin, etoposide, and vorinostat in MM cells.

Conclusions:

• Bufalin is a novel inhibitor of PARP1.
• Bufalin exhibits anti-myeloma activity by inducing apoptosis and cell cycle arrest, partly mediated through PARP1.
• Bufalin demonstrates potential as a therapeutic agent for MM, both as a single agent and in combination therapy.