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TP5: A Novel Therapeutic Approach Targeting Aberrant and Hyperactive CDK5/p25 for the Treatment of Colorectal
Niranjana Amin1, Herui Wang2, Qi Song2
1National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892, USA.
Abstract:
Colorectal carcinoma (CRC) is a prevalent cancer worldwide with a high mortality rate. Evidence suggests that increased expression of Cyclin-dependent kinase 5 (CDK5) contributes to cancer progression, making it a promising target for treatment. This study examined the efficacy of selectively inhibiting CDK5 in colorectal carcinoma using TP5, a small peptide that selectively inhibits the aberrant and hyperactive CDK5/p25 complex while preserving physiological CDK5/p35 functions. We analyzed TP5's impact on CDK5 activity, cell survival, apoptosis, the cell cycle, DNA damage, ATM phosphorylation, and reactive oxygen species (ROS) signaling in mitochondria, in CRC cell lines, both alone and in combination with chemotherapy. We also assessed TP5's efficacy on a xenograft mouse model with HCT116 cells. Our results showed that TP5 decreased CDK5 activity, impaired cell viability and colony formation, induced apoptosis, increased DNA damage, and led to the G1 phase arrest of cell cycle progression. In combination with irinotecan, TP5 demonstrated a synergy by leading to the accumulation of DNA damage, increasing the γH2A.X foci number, and inhibiting G2/M arrest induced by Sn38 treatment. TP5 alone or in combination with irinotecan increased mitochondrial ROS levels and inhibited tumor growth, prolonging mouse survival in the CRC xenograft animal model. These results suggest that TP5, either alone or in combination with irinotecan, is a promising therapeutic option for colorectal carcinoma.
Insights
TP5 peptide effectively inhibits Cyclin-dependent kinase 5 (CDK5) in colorectal carcinoma (CRC). This targeted therapy reduces tumor growth and increases survival, offering a promising new treatment option for CRC patients.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Colorectal carcinoma (CRC) is a leading cause of cancer mortality globally.
- Aberrant Cyclin-dependent kinase 5 (CDK5) activity is implicated in CRC progression.
- Targeting CDK5 presents a potential therapeutic strategy for CRC.
Purpose of the Study:
- To evaluate the efficacy of TP5, a selective CDK5 inhibitor, in colorectal carcinoma.
- To investigate TP5's effects on CRC cell lines and a xenograft mouse model.
- To assess TP5's synergistic potential with chemotherapy.
Main Methods:
- TP5 was tested on CRC cell lines for its impact on CDK5 activity, cell viability, apoptosis, cell cycle, DNA damage, and reactive oxygen species (ROS).
- TP5 was evaluated alone and in combination with irinotecan.
- Efficacy was assessed in a HCT116-based CRC xenograft mouse model.
Main Results:
- TP5 significantly reduced CDK5 activity, impaired cell viability, induced apoptosis, and caused G1 cell cycle arrest.
- TP5 enhanced chemotherapy effects by increasing DNA damage and inhibiting G2/M arrest when combined with irinotecan.
- TP5 treatment, alone or with irinotecan, elevated mitochondrial ROS and inhibited tumor growth, extending survival in mice.
Conclusions:
- TP5 demonstrates potent anti-cancer activity against colorectal carcinoma by inhibiting CDK5.
- TP5 shows promise as a monotherapy or in combination with irinotecan for CRC treatment.
- Targeted inhibition of CDK5 with TP5 represents a viable therapeutic strategy for colorectal carcinoma.
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