Phenanthridine PJ34 Causes Fast Cell Death During Cancer Cell Mitosis
Proteins that can be specifically modified during mitosis, the division process, to unleash an inherent death mechanism that self-eradicates duplicating cancer cells have been identified by researchers at Tel Aviv University.
Many cancer patients struggle with the adverse effects of chemotherapy, still the most prescribed cancer treatment. For patients with pancreatic cancer and other aggressive cancers, the forecast is more grim: there is no known effective therapy.
“The discovery of an exclusive mechanism that kills cancer cells without impairing healthy cells, and the fact that this mechanism works on a variety of rapidly proliferating human cancer cells, is very exciting. According to the mechanism we discovered, the faster cancer cells proliferate, the faster and more efficiently they will be eradicated. The mechanism unleashed during mitosis may be suitable for treating aggressive cancers that are unaffected by traditional chemotherapy.
Our experiments in cell cultures tested a variety of incurable human cancer types; breast, lung, ovary, colon, pancreas, blood, brain. This discovery impacts existing cancer research by identifying a new specific target mechanism that exclusively and rapidly eradicates cancer cells without damaging normally proliferating human cells.”
Mitotic Spindle Modification
The newly-discovered mechanism involves the modification of specific proteins that affect the construction and stability of the spindle, the microtubular structure that prepares duplicated chromosomes for segregation into “daughter” cells during cell division.
The researchers found that certain compounds called Phenanthridine derivatives were able to impair the activity of these proteins, which can distort the spindle structure and prevent the segregation of chromosomes. Once the proteins were modified, the cell was prevented from splitting, and this induced the cell’s rapid self-destruction.
“The mechanism we identified during the mitosis of cancer cells is specifically targeted by the Phenanthridine derivatives we tested,” Prof. Cohen-Armon said. “However, a variety of additional drugs that also modify these specific proteins may now be developed for cancer cell self-destruction during cell division. The faster the cancer cells proliferate, the more quickly they are expected to die.”
The phenanthrenes PJ34, Phen and Tiq-A, the researchers found, modify kinesins (HSET/kifC1 and kif18A) and NuMA (nuclear mitotic apparatus protein) in a variety of human cancer cells. The most efficient cell killing activity was seen with phenanthridine PJ34, which caused significantly smaller aberrant spindles.
Aberrant spindles and impaired spindle poles in human cancer cells treated with the phenanthridine PJ34. (A) Small aberrant spindles were identified by confocal microscopy in randomly scanned human breast cancer MDA-MB-231 cells incubated with PJ34 (20 μM, 27 h). Spindles were immunolabeled for HSET/kifC1 (green) bound to microtubules. Similarly immunolabeled spindles are not impaired in PJ34 treated normal human breast epithelial cells MCF10A. Bars indicate the spindle length measured by the scale bar (n = 20; 3 different experiments), 95% of the spindles in MDA-MB-231 cells were shorter, 60 ± 5% in size. (B) Upper panel: Impaired spindle poles were identified in randomly scanned fixed MDA-MB-231 cells treated with PJ34 (20 μM, 27 h). Microtubules immunolabeled by α- tubulin (green), centrosomes immunolabeled by γ-tubulin (red) and chromosomes stained by DAPI (blue) are displayed. Lower panel: Spindle poles were not impaired in randomly scanned normal epithelial MCF10A cells treated with PJ34 (20 μM, 27 h). Microtubules identified by immunolabeled HSET14/kifC1 (green), centrosomes immunolabeled for γ-tubulin (red) and chromosomes stained by DAPI (blue) are displayed. The sampled spindles represent 95% of randomly scanned spindles (n = 20) of cancer MDA-MB-231 cells and all the randomly scanned spindles (n = 20) of normal epithelial MCF10A cells in 3 different experiments. CC BY 3.0
Tumor Growth Stopped
Research was conducted using both cancer cell cultures and mice transplanted with human cancer cells. The scientists harnessed biochemical, molecular biology and imaging technologies to observe the mechanism in real time.
In addition, mice transplanted with triple negative breast cancer cells, currently resistant to available therapies, revealed the arrest of tumor growth.
“Identifying the mechanism and showing its relevance in treating developed tumors opens new avenues for the eradication of rapidly developing aggressive cancers without damaging healthy tissues,” said Prof. Cohen-Armon.
The researchers are currently investigating the potential of one of the Phenanthridine derivatives to treat two aggressive cancers known to be unresponsive to current chemotherapy: pancreatic cancer and triple negative breast cancer.
The work was supported by ICRF, Novartis, and a joint grant of Sheba Medical center and RAMOT.