A small-molecule induces apoptosis and suppresses metastasis in pancreatic cancer cells
Dan Li1, Zuojia Liu, Wenjing Zhao
1State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, China.
Abstract:
Pancreatic cancer is one of the most malignant tumor diseases with the characters of aggressive growth and metastasis. With the inefficiency of the current therapeutics, new potential targets and new therapeutic agents for healing of pancreatic cancer are critically needed. We have previously found a small molecule, named 4-tert-butyl-2-[(cyclohexylamino) methyl]-6-methylphenol (TBMMP, NSC number: 48160), which can freeze the intermediate of Ras-GTP hydrolysis in the open non-signaling conformation with high affinity and high specificity in silico. In this work, we studied the effect and mechanism of TBMMP on two pancreatic cancer cell lines, CFPAC-1 and BxPC-3. The results showed that TBMMP could restrain the growth of the pancreatic cancer cells with IC(50) value 84.3 μM for CPFAC-1 and 94.5 μM for BxPC-3, respectively. Additionally, TBMMP increased cytochrome c release, reduced mitochondrial membrane potential, activated caspase-3, -9, elevated ROS and increased expression of the Bax in the pancreatic cancer cell lines. The results indicated that TBMMP induced the apoptosis of pancreatic cancer cells through the mitochondrial pathway. Further, we also found that TBMMP could suppress the metastasis of both pancreatic cancer cells in vitro. Taken together, we proposed that TBMMP might be a therapeutic potential lead for treating patients with pancreatic cancer.
Insights
The small molecule 4-tert-butyl-2-[(cyclohexylamino) methyl]-6-methylphenol (TBMMP) effectively inhibits pancreatic cancer cell growth and metastasis. TBMMP induces apoptosis via the mitochondrial pathway, suggesting its potential as a novel pancreatic cancer therapeutic.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Pancreatic cancer exhibits aggressive growth and metastasis, necessitating novel therapeutic strategies due to current treatment limitations.
- A previously identified small molecule, 4-tert-butyl-2-[(cyclohexylamino) methyl]-6-methylphenol (TBMMP), demonstrated in silico ability to inhibit Ras-GTP hydrolysis.
- The specific mechanism and efficacy of TBMMP in pancreatic cancer require further investigation.
Purpose of the Study:
- To investigate the anti-cancer effects and underlying mechanisms of TBMMP on pancreatic cancer cell lines.
- To evaluate TBMMP's impact on cell proliferation, apoptosis, and metastasis in pancreatic cancer models.
- To assess TBMMP's potential as a therapeutic lead for pancreatic cancer treatment.
Main Methods:
- Treatment of CFPAC-1 and BxPC-3 pancreatic cancer cell lines with TBMMP.
- Assessment of cell growth inhibition using IC50 values.
- Analysis of apoptosis-related markers including cytochrome c, mitochondrial membrane potential, caspase-3, caspase-9, reactive oxygen species (ROS), and Bax expression.
- In vitro evaluation of TBMMP's effect on cancer cell metastasis.
Main Results:
- TBMMP significantly inhibited the growth of both pancreatic cancer cell lines with IC50 values of 84.3 μM (CFPAC-1) and 94.5 μM (BxPC-3).
- TBMMP induced apoptosis through the mitochondrial pathway by increasing cytochrome c release, decreasing mitochondrial membrane potential, activating caspases-3 and -9, elevating ROS, and upregulating Bax expression.
- TBMMP demonstrated a suppressive effect on the in vitro metastasis of pancreatic cancer cells.
Conclusions:
- TBMMP exhibits significant anti-proliferative and anti-metastatic effects on pancreatic cancer cells.
- The mechanism of TBMMP-induced cell death involves the mitochondrial apoptotic pathway.
- TBMMP represents a promising therapeutic lead for the development of novel pancreatic cancer treatments.
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