Platinum-Paeonol Complexes as ERK Inhibitors To Restrain Melanoma and Relieve Cancer Pain

Area of Science:

• Oncology
• Pharmacology
• Cancer Biology

Background:

• Melanoma is a challenging skin cancer with limited treatment options.
• The ERK pathway is crucial for melanoma progression, metastasis, and pain.
• Current therapies often show poor response rates in melanoma patients.

Purpose of the Study:

• To synthesize and evaluate platinum-paeonol complexes (PAP and DPAP) for antimelanoma activity and pain relief.
• To investigate the molecular mechanisms underlying DPAP's effects on melanoma.
• To explore DPAP's potential in combination therapy with immunotherapy.

Main Methods:

• In vitro and in vivo studies using melanoma models.
• Assessment of DNA and mitochondrial damage, apoptosis induction.
• Analysis of ERK pathway signaling (p-MEK1/2, p-ERK1/2), angiogenesis, and PD-L1 expression.
• Evaluation of cancer pain relief in mouse models by examining spinal cord neuroinflammation.

Main Results:

• DPAP demonstrated significant in vitro and in vivo antimelanoma efficacy.
• DPAP induced apoptosis via mitochondrial damage and inhibited melanoma metastasis and angiogenesis by suppressing p-MEK1/2 and p-ERK1/2.
• DPAP alleviated cancer pain by inhibiting p-ERK1/2 and COX-2 in nerve cells and reducing spinal cord neuroinflammation.
• DPAP uniquely upregulated programmed cell death ligand 1 (PD-L1), enhancing tumor susceptibility to immunotherapy.
• Combination therapy with DPAP and anti-PD-1 antibody significantly improved antitumor outcomes.

Conclusions:

• DPAP is a promising therapeutic agent for melanoma, exhibiting direct antitumor effects, pain relief, and immune modulation.
• DPAP's ability to upregulate PD-L1 creates a favorable microenvironment for combination with PD-1 inhibitors.
• Combined DPAP and anti-PD-1 therapy offers a potent strategy to overcome melanoma refractoriness and improve patient outcomes.