Cancer cell mechanical behavior a target for drug treatment [PreClinical]

1. Following a chemical library screen, the compound 4-hydroxyacetophenone (4-HAP) was found to target mechanical changes in cell shape important for cell division.

2. When treated with 4-HAP, deformable pancreatic cancer cells became stiffer and exhibited decreased metastatic behavior.

Evidence Rating Level: 3 (Average)

Study Rundown: Current chemotherapy drugs generally target biochemical molecules that play a role in cancer cells’ aberrant behavior, such as uncontrolled division. However in addition to biochemical processes, cancer cells also exhibit distinct mechanical properties; for example, the increased deformability of cancer cells is believed to contribute to metastasis. In this study, a high throughput screen was performed on a library of chemical compounds to identify potential drugs that alter cell mechanics. Specifically, image analysis was used to evaluate whether the compounds inhibited cytokinesis, the stage of cell division where one cell is physically divided into two. The screen led to the identification of the small molecule 4-HAP. 4-HAP was found to target the protein myosin II, which generates the mechanical forces necessary for cell shape and movement. When pancreatic cancer cells were treated with 4-HAP, they became stiffer. Notably, the treated cells showed decreased invasion and migration behaviors that are characteristic of metastatic cancer cells. While this study demonstrated the potential of 4-HAP in improving the mechanical properties of cancer cells, because this proof of concept study was performed in vitro, additional evaluation of 4-HAP in animal models of cancer will be necessary. Overall, the study highlights the potential for drug discovery in the area of cell mechanics.

Click to read the study in PNAS

Relevant Reading: Biomechanics and biophysics of cancer cells

In-Depth [in vitro study]: Over 22,000 compounds in the commercially available ChemBridge DIVERSet chemical library were screened for activity in cell mechanical processes. As measured by image analysis, inhibition of cytokinesis was used as the readout for the high throughput screen. Because cytokinesis is a well-understood process that involves mechanical changes in cell shape, it was selected as a representative cell mechanical property. After the library compound carbamate-7 was identified to have an inhibitory effect on cytokinesis, further analysis showed that its degradation product 4-HAP was responsible for the activity of interest.

In cells treated with 4-HAP, the accumulation of the mechanoenzyme myosin II resulted in increased cortical tension (p=0.01), the force that maintains cell shape. To determine the potential of 4-HAP in improving cancer cell mechanics, the patient-derived pancreatic ductal adenocarcinoma metastatic cell line ASPC-1 was used. Compared to normal pancreatic cells, ASPC-1 cells were significantly less stiff. Following treatment with 4-HAP, ASPC-1 cell stiffness increased. Furthermore, treated ASPC-1 cells showed decreased invasion and migration behavior in a dose-dependent fashion. At the highest tested 4-HAP concentration of 50µM, ASPC-1 cells exhibited significantly less invasion and migration behavior than the control of no drug treatment (p<0.0001).

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Image: PD

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