Label-Free Target Identification Reveals the Anticancer Mechanism of a Rhenium Isonitrile Complex

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Biochemistry

Background:

• Platinum-based drugs like cisplatin and carboplatin target DNA, but their efficacy is limited by side effects and resistance.
• Rhenium-based complexes offer a promising alternative with potentially different molecular targets and improved selectivity.
• Understanding the molecular mechanisms of novel anticancer agents is crucial for developing more effective therapies.

Purpose of the Study:

• To elucidate the molecular mechanism of action for tricarbonyl rhenium isonitrile polypyridyl (TRIP) complexes.
• To identify the specific molecular target of TRIP complexes.
• To investigate the downstream signaling pathways activated by TRIP complex interaction with its target.

Main Methods:

• Inductively coupled plasma mass spectrometry (ICP-MS) to confirm the target type.
• Label-free target identification to pinpoint the specific protein target.
• In vitro assays to evaluate the inhibition of chaperone function.
• Mitochondrial protein analysis and Western blotting to assess pathway activation.

Main Results:

• TRIP complexes were confirmed to target proteins, not DNA.
• Heat shock protein 60 (HSP60) was identified as the direct molecular target of TRIP complexes.
• TRIP directly inhibits HSP60 chaperone activity, leading to misfolded protein accumulation in mitochondria.
• This accumulation activates the mitochondrial unfolded protein response (mtUPR)-mediated apoptotic pathway involving JNK2/AP-1/CHOP.

Conclusions:

• TRIP complexes represent a novel class of anticancer agents with a unique mechanism of action targeting HSP60.
• Inhibition of HSP60 chaperone function by TRIP complexes triggers mitochondrial dysfunction and induces cancer cell apoptosis.
• TRIP complexes hold potential as selective anticancer therapeutics with a distinct mode of action compared to platinum-based drugs.