Targeting RAS-RAF pathway significantly improves antitumor activity of Rigosertib-derived platinum(IV) complexes and...

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• The RAS-RAF pathway is crucial in regulating cancer cell proliferation, apoptosis, and drug resistance.
• Targeting this pathway offers a promising strategy for developing novel cancer therapeutics.

Purpose of the Study:

• To synthesize and evaluate novel multifunctional platinum(IV) complexes conjugated with a RAS/CRAF interference agent.
• To investigate the in vitro and in vivo anti-tumor efficacy and mechanisms of action of these complexes.

Main Methods:

• Synthesis of eleven Pt(IV) complexes via ester bond conjugation.
• In vitro cytotoxicity assays against various cancer and normal cell lines, including cisplatin-resistant lines.
• Cell cycle analysis, apoptosis assays, and Western blotting to elucidate mechanisms of action.
• In vivo studies using a xenograft subcutaneous model of A549 lung cancer.

Main Results:

• All synthesized Pt(IV) complexes demonstrated significant anti-tumor activity, with IC50 values superior to cisplatin.
• Complex 26 exhibited potent cytotoxicity against both sensitive and cisplatin-resistant cancer cells, while sparing normal cells.
• Complex 26 induced G2/M cell cycle arrest, disrupted the MAPK signaling pathway, and triggered apoptosis.
• In vivo, complex 26 effectively suppressed tumor growth without causing significant body weight loss.

Conclusions:

• Multifunctional Pt(IV) complexes targeting the RAS-RAF pathway represent a promising new class of anti-cancer agents.
• Complex 26 shows excellent therapeutic potential due to its potent efficacy, targeted action, and favorable safety profile.
• These findings support further development of Pt(IV) complexes for overcoming cancer drug resistance and improving treatment outcomes.