Anti-tumor effects of quinolines
Reference Number: K 07-11
Inventors: Nguyen, Thu A.; Hua, Duy
Owner: Kansas State University Research Foundation
Researchers at Kansas State University have discovered a class of compounds (quinolines; code name PQ) that has shown inhibitory effects on human breast and colon cancer. Cancer cells exhibit defects in intracellular and intercellular communication that contribute to the loss of tissue homeostasis. Intercellular communication in many organs is maintained via gap junction intercellular channels (GJIC).
A number of quinoline analogs have been synthesized.The quinoline analog classified as PQ1 alone showed approximately 80-95% growth attenuation in multiple breast and colorectal cancer cell lines in a colony assay (cancer cell – specific growth assay conducted in soft agar). Moreover, the effect of PQ1 on these cancer cells showed a 20-50% increase in GJIC, suggesting the gain of GJIC in cancer cells plays a critical role in the anti-tumor treatment. However, PQ2 has an opposite effect on cancer cell lines.
The researchers found that PQ2 exhibit approximately 2.6-fold increase in a colony growth assay and caused a 50% decrease in GJIC. Taken together these results strongly indicate that quinolines are effective chemotherapeutic agents for multiple cancers including breast and colon cancer through enhancement of GJIC.
The researchers are currently extending their study to a drug-protein interaction, a mouse in vivo study, and quinoline-mediated mechanism of action. They are also testing the effect of quinolines on the growth of other types of human cancer cells such as prostate cancer, glioma, pancreatic cancer etc.
A. T47D cells
B. Caco-2 cells
Figure 1. Colony Growth using soft agar. (A) T47D human breast cancer and (B) Caco-2 human colorectal cancer cells were treated with 10 µl of various quinolines for 7 days. Base agar plates were prepared containing 0.8% agar and 0.4% agar in Ham’s F12. Cells (5 × 104 cells/33 mm well) were suspended in 100µl of Ham’s F12 with 0.4% agar and plated. These plates were maintained at 37°C for 7 days and examined for the presence of colonies. Individual colonies of 40 µm or greater were examined. The results demonstrated that PQ1 and PQ3 showed approximately 80-95% growth attenuation in both cancer cell lines compared to control. PQ4 only has an inhibitory effect on T47D breast cancer cells, not Caco-2 colorectal cancer cells. However, PQ2 caused a 2.6- and 2.5-fold increase in colony growth in T47D and Caco-2 colony growth compared to DMSO, respectively. PQ5 has no effect in both cell lines. These suggest that quinoline derivatives, PQ1 and PQ3, have anti-tumor effect on breast and colorectal cancer.
Figure 2. Gap Junction Activity using Dye-Coupling Assay T47D cells were treated with low (500nM) and high (10µm concentrations of PQ1 and control (succinic acid, solvent) for 24 hours. Monolayers of acceptor cell population were grown on 25-cm2 flasks in the presence of Vibrant DiD. Vybrant DiD in acceptor cells was not able to pass through the gap junctions because of its hydrophobic property. Single cell suspensions of donor treated cells were prepared, labeled with 0.05 µg/ml calcein-AM, incubated at 37°C for 5 minutes. Quantification of dye coupling between the donor and acceptor cells was assessed by dual-excitation flow cytometry. The results demonstrated that 10 µM of PQ1 caused a 1.5-fold increase of gap junction activity compared to control.