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Researchers have made different investigations to understand the mechanism of tumorigenesis in gastrointestinal cancers. They found that overexpression of the cyclin D2 and CDK4/6 and loss of function of the APC in the intestinal epithelial cancer, suggesting that deregulation of the CDK4/6 is required for the enterocyte to proliferate and form adenoma.
53 out of the 74 patients examined with colorectal carcinoma, p16INK4a and CDK4 were found to be overexpressed as compared to the adjacent normal tissue while all these patients were found to have an overexpression of the CDK4. In another study, about 55% of the 602 patients with colon cancer were diagnosed to have an overexpression of the cyclin D1.
In the same manner, researchers reported overexpression of the CDK2 in the colon cancer tumor cells than in the adenoma cells and overexpression of the CDK1 in the tumor specimens from 254 patients with stage 2 colon cancer.
Researchers have evaluated 116 patients with esophageal cancer and found 10% of the tumors contained amplification of the CDK4 gene and associated with the worse survival. While only 4 out of the 116 tumors were found to have amplification of both CDK4 and CDK6 and associated with poor survival.
Gastric cancer carried out in the 260 patients, about 48% were found to have overexpression of the cyclin D1, D2, and E while in most of the cases, the overexpression of the CDK4, cyclin D2 and loss of p27 was found to be correlated with the tumor progression.
Pancreatic and Hepatocellular Cancer
The researchers have found overexpression of the cyclin D1 in 68% of the pancreatic cancer specimens while 10% of the pancreatic intraepithelial neoplasia was found to have increased expression of the CDK2 and CDK4. Similarly, researchers have also observed the inactivation of p16INK4a in about 83% of the patients with pancreatic cancer tumors.
A study carried out by Ito et al in 104 patients with hepatocellular carcinoma, p21Kip1 and p16INK4a were overexpressed while 37 of the 104 patients were found to have an overexpression of the cyclin D1.
Cell cycle abnormalities were also commonly observed in the biliary neoplasm. A study conducted in the patients with intrahepatic cholangiocarcinoma, 62% of the patients were found to have overexpression of the cyclin D1 while the loss of p16INK4a and p27Kip1 were observed in 31% and 14% of the patients respectively. Similarly, about 41% of the gallbladder cancers were detected to have an overexpression of the cyclin D1.
All these taken together suggest that cell cycle abnormalities are more common in the gastrointestinal tumors and overexpression of the cyclin-dependent protein kinases and cyclins and loss of CDKis such as p21Cip1 and p27Kip1 are associated with the progression of the tumor phenotypes and poor prognosis. Therefore, targeting the cell cycle represents a promising and most important strategy for the treatment of gastrointestinal cancers.
Preclinical and Clinical Data for the Cell Cycle Inhibitors
Use of PD-0332991 as a CDK inhibitor
Researchers have administered PD-0332991, a CKD inhibitor in the mice bearing Colo-205 human colon carcinoma and found a marked regression of the tumor while retraction of the PD-0332991 didn’t develop any resistance.
Administration of the PD-0332991 eliminated the phosphorylated retinoblastoma and downregulated the E2F regulated genes that cause cell cycle arrest at the G1 phase. It was also found to inhibit the cell cycle progression irrespective of the retinoblastoma status.
Use of other CDK inhibitors
In the same way, a CDK2 inhibitor butyrolactone-I was found to inhibit the proliferation of the colon cancer cell lines leading to apoptosis in the LoVo cell lines. And another CDK2 inhibitor, SU 9516 was found to inhibit the CDK2 leading to either a G0-G1 or a G2-M arrest in the human colon cancer cell lines.
Flavopiridol in combination with radiation therapy in the human esophageal adenocarcinoma cells found that cell cycle arrest at the G1 phase. In addition, it causes radiation-induced apoptosis and inhibition of the transcription activity. These results reveal that CDK inhibitors can be combined with radiation therapy to treat cancer.
Studies in the pancreatic cell lines reveal that the CDK inhibitor flavopiridol in combination with gemcitabine, a chemotherapeutic agent for cancer, has a synergistic activity. Flavopiridol is the most extensively studied CDK inhibitor for gastrointestinal cancers. It inhibits the CDK1, CDK2, CDK4, CDK7, and CDK9 while it also promotes the apoptosis induced by chemotherapeutic agents.
In conclusion, cell cycle inhibition is an effective strategy to cancer treatment, because of the role of the cyclin and CDKs in the cell in the complexity of the cell cycle. CDKis can effectively be used to treat the cell cycle abnormalities commonly seen in gastrointestinal tumors. Among the different types of CDKis, flavopiridol and PD-0332991 are the best-studied CDK inhibitors with some disappointing results and can be used as a monotherapy or in a combination with other therapies such as radiation therapy and chemotherapy.
Reference: The American Journal of Pathology (Cyclin-Dependent Kinase Inhibitors and the Treatment of Gastrointestinal Cancers)
Article DOI: 10.1016/j.ajpath.2015.01.008