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Updated: May 4, 2026
High-throughput Identification of Synergistic Drug Combinations by the Overlap2 Method
Published on: May 21, 2018
Chloroquine synergizes with FTS to enhance cell growth inhibition and cell death
Eran Schmukler1, Eya Wolfson, Roni Haklai
1Department of Neurobiology. Tel-Aviv University, Ramat-Aviv, Israel.
Abstract:
The Ras family of small GTPases transmits extracellular signals that regulate cell growth, differentiation, motility and death. Ras signaling is constitutively active in a large number of human cancers. Ras can also regulate autophagy by affecting several signaling pathways including the mTOR pathway. Autophagy is a process that regulates the balance between protein synthesis and protein degradation. It is important for normal growth control, but may be defective in diseases. Previously, we have shown that Ras inhibition by FTS induces autophagy, which partially protects cancer cells and may limit the use of FTS as an anti-cancer drug. Since FTS is a non toxic drug we hypothesized that FTS and chloroquine (an autophagy inhibitor) will synergize in cell growth inhibition and cell death. Thus, in the present study, we explored the mechanism of each individual drug and their combined action. Our results demonstrate that in HCT-116 and in Panc-1 cells, FTS induces autophagy, which can be inhibited by chloroquine. Furthermore, the combined treatment synergistically decreased the number of viable cells. Interestingly, the combined treatment enhanced apoptotic cell death as indicated by increased sub-G1 cell population, increased Hoechst staining, activation of caspase 3, decrease in survivin expression and release of cytochrome c. Thus, chloroquine treatment may promote FTS-mediated inhibition of tumor cell growth and may stimulate apoptotic cell death.
Insights
Combining FTS with chloroquine, an autophagy inhibitor, synergistically reduces cancer cell viability and enhances apoptosis. This combination therapy shows promise for cancer treatment by overcoming FTS-induced autophagy-mediated protection.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Ras signaling is crucial for cell growth and survival, and its aberrant activation drives many human cancers.
- Ras signaling influences autophagy, a cellular degradation process that can impact cancer cell survival and drug resistance.
- FTS, a Ras inhibitor, induces autophagy, which may limit its efficacy as an anti-cancer drug.
Purpose of the Study:
- To investigate the synergistic effects of FTS and chloroquine (an autophagy inhibitor) on cancer cell growth and death.
- To elucidate the underlying mechanisms of FTS and chloroquine's combined action in cancer cells.
Main Methods:
- Treatment of HCT-116 and Panc-1 cancer cells with FTS and chloroquine, individually and in combination.
- Assessment of autophagy induction and inhibition.
- Evaluation of cell viability, apoptosis markers (sub-G1 population, Hoechst staining, caspase 3 activation, survivin expression, cytochrome c release).
Main Results:
- FTS treatment induced autophagy in cancer cells, which was effectively inhibited by chloroquine.
- Combined FTS and chloroquine treatment synergistically decreased cancer cell viability.
- The combination therapy significantly enhanced apoptotic cell death, evidenced by increased caspase 3 activation and cytochrome c release, and decreased survivin expression.
Conclusions:
- Chloroquine can overcome FTS-induced autophagy-mediated cancer cell protection.
- The combination of FTS and chloroquine demonstrates synergistic anti-cancer effects, promoting apoptosis and inhibiting tumor cell growth.
- This combination strategy holds potential for improving cancer therapy outcomes.
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