A small natural molecule CADPE kills residual colorectal cancer cells by inhibiting key transcription factors and translation initiation factors.

Residual disease is the major cause for colorectal cancer (CRC) relapse. Herein, we explore whether and how a natural molecule CADPE killed heterogenic populations in a panel of CRC cell lines with KRAS/BRAF mutations that are natively resistant to EGFR- or VEGFR-targeted therapy, without sparing persistent cells, a reservoir of the disease relapse. Results showed that CADPE killed the tumor bulk and residual cells in the panel of CRC cell lines, rapidly inactivated c-Myc, STAT3, and NF-κB, and then decreased the protein levels of key signaling molecules for CRC, such as ß-catenin, Notch1, and the nodes of mTOR pathways; eukaryotic translation initiation factors (eIF4F); anti-apoptotic proteins (Bcl-xl, Mcl-1, and survivin); and stemness-supporting molecules (CD133, Bim-1, and VEGF). In terms of mechanism of action, concurrent downregulation of Mcl-1, Bcl-xl, and survivin was necessary for CADPE to kill CRC bulk cells, while additional depletion of CD133 and VEGF proteins was required for killing the residual CRC cells. Moreover, the disabled c-Myc, STAT3, NF-κB, and eIF4F were associated with the broadly decreased levels of anti-apoptosis proteins and pro-stemness proteins. Consistently, CADPE suppressed CRC tumor growth associated with robust apoptosis and depleted levels of c-Myc, STAT3, NF-κB, eIF4F, anti-apoptotic proteins, and pro-stemness proteins. Our findings showed the promise of CADPE for treating CRC and suggested a rational polytherapy that disables c-Myc, STAT3, NF-κB, and eIF4F for killing CRC residual disease.

Anti-colorectal cancer effects of tripolinolate A from Tripolium vulgare.

Tripolinolate A (TLA) is recently identified as a new compound from a halophyte plant Tripolium vulgare and has been shown to have significant in vitro activity against the proliferation of colorectal cancer and glioma cells. This study was designed to further investigate the effects of TLA on the proliferation of human normal cells, and the apoptosis and cell cycle in colorectal cancer cells, and the growth of tumors in the colorectal cancer-bearing animals. The data obtained from this study demonstrated that: 1) TLA had much less cytotoxicity in the human normal cells than the colorectal cancer cells; 2) TLA remarkably induced apoptosis in the human colorectal cancer cells and blocked cell cycle at G2/M phase, and 3) TLA had significant anti-colorectal cancer activity in the tumor-bearing animals.

Association between the CDC6 G1321A polymorphism and the risk of cervical cancer.

INTRODUCTION: Cell division cycle protein 6 (CDC6) plays critical roles in DNA replication and carcinogenesis. The biological significance of the CDC6 G1321A polymorphism (V441I, rs13706) on cervical carcinogenesis is still unknown. Here, we examined the potential influence of this polymorphism on cell proliferation and the individual's susceptibility to cervical cancer. METHODS: We genotyped the CDC6 G1321A polymorphism in 87 cervical cancer cases and 110 healthy female subjects. Unconditional logistic regression analysis was used to estimate the association between the genotypes and the risk of cervical cancer. The BrdU incorporation assay was applied to analyze the effect of this polymorphism on cell proliferation. RESULTS: Compared with the GG homozygotes, the cervical cancer risk was significantly reduced in the individuals with the heterozygous AG genotype (odds ratio [OR], 0.53; 95% confidence interval [CI], 0.28-0.98; P = 0.042) or the homozygous AA genotype (OR, 0.29; 95% CI, 0.09-0.89; P = 0.030). Further stratified analyses showed that the decreased risk of cervical cancer was more evident among younger subjects (≤44 years old) with the AG or AA genotypes (OR, 0.44; 95% CI, 0.21-0.92; P = 0.029 and OR, 0.12; 95% CI, 0.03-0.61; P = 0.010, respectively). The BrdU incorporation assay showed that 293T cells transfected with CDC6-441I (1321A) had a lower proliferation rate in comparison with those transfected with CDC6-441V (1321G), although the difference did not reach statistical significance at the 0.05 level. CONCLUSIONS: The CDC6 G1321A polymorphism may contribute to the risk of cervical cancer. Further studies with more subjects and in diverse ethnic populations are necessary to confirm the general validity of our findings.