The Multikinase Inhibitor AD80 Induces Mitotic Catastrophe and Autophagy in Pancreatic Cancer Cells

by Selleckchem | Dec 10 2023

Significant advances in understanding the molecular complexity of the development and progression of pancreatic cancer have been made, but this disease is still considered one of the most lethal human cancers and needs new therapeutic options. In the present study, the antineoplastic effects of AD80, a multikinase inhibitor, were investigated in models of pancreatic cancer. AD80 reduced cell viability and clonogenicity and induced polyploidy in pancreatic cancer cells. At the molecular level, AD80 reduced RPS6 and histone H3 phosphorylation and induced γH2AX and PARP1 cleavage. Additionally, the drug markedly decreased AURKA phosphorylation and expression. In PANC-1 cells, AD80 strongly induced autophagic flux (consumption of LC3B and SQSTM1/p62). AD80 modulated 32 out of 84 autophagy-related genes and was associated with vacuole organization, macroautophagy, response to starvation, cellular response to nitrogen levels, and cellular response to extracellular stimulus. In 3D pancreatic cancer models, AD80 also effectively reduced growth independent of anchorage and cell viability. In summary, AD80 induces mitotic aberrations, DNA damage, autophagy, and apoptosis in pancreatic cancer cells. Our exploratory study establishes novel targets underlying the antineoplastic activity of the drug and provides insights into the development of therapeutic strategies for this disease.

Comments:

The findings described in the study highlight several key aspects regarding the potential therapeutic effects of AD80 in pancreatic cancer:

### 1. **Antineoplastic Effects:**
- **Cell Viability and Clonogenicity:** AD80 significantly reduced cell viability and clonogenicity in pancreatic cancer cells. This suggests that the drug hampers the cancer cells' ability to grow and form colonies, indicating potential effectiveness in limiting tumor progression.
- **Polyploidy Induction:** AD80 induced polyploidy in pancreatic cancer cells. Polyploidy, or cells having more than two paired sets of chromosomes, can disrupt normal cell division processes, leading to cell death. This effect can be harnessed for anti-cancer therapies.

### 2. **Molecular Mechanisms:**
- **Phosphorylation and Cleavage:** AD80 reduced the phosphorylation of proteins like RPS6 and histone H3 and induced γH2AX and PARP1 cleavage. These molecular events indicate disruption in cell signaling pathways, DNA damage, and activation of apoptosis, all of which contribute to halting cancer cell growth and inducing cell death.
- **AURKA Modulation:** AD80 markedly decreased AURKA phosphorylation and expression. AURKA is a protein associated with cell division and is often overexpressed in cancer. Inhibiting AURKA can disrupt cell division, leading to cancer cell death.

### 3. **Autophagy Modulation:**
- **Autophagic Flux:** AD80 induced autophagic flux, a cellular process where damaged cellular components are degraded and recycled. This is a critical mechanism for maintaining cellular homeostasis and can lead to cell death if dysregulated.
- **Gene Modulation:** AD80 affected the expression of multiple autophagy-related genes. This modulation indicates a complex influence on the cellular machinery, potentially contributing to its anti-cancer effects.

### 4. **3D Pancreatic Cancer Models:**
- **Anchorage-Independent Growth:** AD80 effectively reduced growth even in 3D models of pancreatic cancer, indicating its potential to inhibit tumor growth in a three-dimensional, physiologically relevant environment.
- **Cell Viability:** The drug also decreased cell viability in these 3D models, reinforcing its effectiveness in inhibiting cancer cell survival and growth in conditions that mimic the human body more closely.

### 5. **Therapeutic Implications:**
- **Target Discovery:** The study identified specific molecular targets affected by AD80, providing valuable information for further research into pancreatic cancer treatments.
- **Therapeutic Development:** These findings provide insights into the development of new therapeutic strategies for pancreatic cancer. Understanding the specific pathways and mechanisms through which AD80 acts can aid in the development of targeted therapies for this lethal disease.

In summary, this study not only elucidates the molecular complexities of AD80's effects on pancreatic cancer cells but also lays the groundwork for the development of novel therapeutic approaches in the battle against this highly aggressive form of cancer. Further research based on these insights could potentially lead to the development of more effective treatments for pancreatic cancer patients.