Abstract
Side effects of anti-cancer drugs are always challenging for effective cancer treatments. The polysaccharides extracted from Phellinus linteus (PLGL) have been widely used in treating cancers. However, the mechanism by which PLGL antagonizes cancerous growth has not been fully investigated. The current study demonstrated that human colon cancer HCT116 and HT29 cells became highly susceptible to cell death when being co-treated with PLGL and low dose of camptothecin11 (CPT11, a topoisomerase inhibitor-based drug), the efficacy of which was comparable as that generated by the high dose of CPT11. However, the co-treatment, unlike high doses of CPT11, was not cytotoxic to the control immortalized colon Caco-2 cells. The co-treatment caused high percentages of the colon cancer cells to accumulate in S phase of the cell cycle, which was also seen in the same cells received the high dose of CPT11 treatment. Chk1 was phosphorylated, and then rapidly degraded in the cancer cells treated with the high dose of CPT11 or co-treatment, but not in the cells treated with PLGL alone or low doses of CPT11. PLGL appeared enhancing CPT11 inhibitory effect on topoisomerase, and Chk1 degradatopm in the cancer cells. Furthermore, cyclin E (clnE) became unstable at the transcription level in co-treated or PLGL-treated colon cancer cells. The data suggested that PLGL functions in two ways to achieve its lethal synergy with CPT11 in colon cancer cells. Our findings are of potential significance as PLGL represents a promising medicine for overcoming the side effects of CPT11 and perhaps also for improving other CPTs-based regimens.
Highlights
Colon malignancy is the second leading cause of cancer mortality worldwide [1,2,3,4]
The current study demonstrated that human colon cancer HCT116 and HT29 cells became highly susceptible to cell death when being co-treated with PLGL and low dose of camptothecin11 (CPT11, a topoisomerase inhibitor-based drug), the efficacy of which was comparable as that generated by the high dose of CPT11
The results suggested that the combination treatment of PLGL and low dose of CPT11 acted in synergy for killing colon cancer cells
Summary
Colon malignancy is the second leading cause of cancer mortality worldwide [1,2,3,4]. A colon cancer cell evolving from colon epithelium usually undergoes a predictable progression of histological alterations and, concurrent genetic and epigenetic changes, which provide a growth advantage for oligo-clonal expansions from pre-malignant stages to cancer. The earliest recognisable lesions in sporadic colon cancer formation seem to be aberrant crypt foci that subsequently progress to adenomas and adenocarcinomas. Sporadic colon cancer is initiated by changes in Wingless (Wnt)-regulated signaling pathways, which permit activation of oncogenes or loss of function of tumor suppressors. Genes mutated or deleted during colon tumorigenesis consist of B-raf, K-ras or p53 [5,6,7,8]. Upon oncogenic activation of K-Ras or B-Raf, several intracellular growth-related signalling www.impactjournals.com/oncotarget pathways are upregulated, resulting in perturbation of cell cycle checkpoints or enhance of pro-survival activities. The prognosis of advanced colon cancer is dismal, and better therapeutics is urgently needed
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