Oncoscience最新文献

Hec1 (Highly expressed in cancer 1) resides in the outer kinetochore where it works to facilitate proper kinetochore-microtubule interactions during mitosis. Hec1 is overexpressed in various cancers and its expression shows correlation with high tumour grade and poor patient prognosis. Chemical perturbation of Hec1 is anticipated to impair kinetochore-microtubule binding, activate the spindle assembly checkpoint (spindle checkpoint) and thereby suppress cell proliferation. In this study, we performed high-throughput screen to identify novel small molecules that target the Hec1 calponin homology domain (CHD), which is needed for normal microtubule attachments. 4 million compounds were first virtually fitted against the CHD, and the best hit molecules were evaluated in vitro. These approaches led to the identification of VTT-006, a 1,2-disubstituted-tetrahydro-beta-carboline derivative, which showed binding to recombinant Ndc80 complex and modulated Hec1 association with microtubules in vitro. VTT-006 treatment resulted in chromosome congression defects, reduced chromosome oscillations and induced loss of inter-kinetochore tension. Cells remained arrested in mitosis with an active spindle checkpoint for several hours before undergoing cell death. VTT-006 suppressed the growth of several cancer cell lines and enhanced the sensitivity of HeLa cells to Taxol. Our findings propose that VTT-006 is a potential anti-mitotic compound that disrupts M phase, impairs kinetochore-microtubule interactions, and activates the spindle checkpoint.

Colorectal cancer is the third most common form of cancer diagnosed and the third leading class for cancer-related deaths. Given the prevalence of colon cancer worldwide, further insight into developing novel and effective prevention and treatment strategies are warranted. The family of plant pigments known as the anthocyanins has been identified with a variety of health benefits including chemopreventive and therapeutic effects. A limitation to current clinical applications of anthocyanins is the high doses that are required. In order to overcome this limitation, we tested the active moiety, anthocyanidins for chemopreventive and therapeutic effects against colorectal cancer in vivo and in vitro. Treatment with native anthocyanidin mixture (Anthos) from bilberry yielded significant antiproliferative activity against colon cancer cells. Anthos treatment led to significant reductions in polyp and tumor counts in vivo. Reduced Src and EGFR phosphorylation was observed with Anthos treatment, which correlated with downstream targets such as PD-L1 and modulation of the colon inflammatory environment. These results provide a promising outlook on the impact of berry Anthos for the treatment and prevention of familial adenomatous polyposis and colorectal cancer. Results from this study also provide novel mechanistic insight into the chemopreventive and therapeutic activities of Anthos.

Although average human life expectancy is rising, the maximum lifespan is not increasing. Leading demographers claim that human lifespan is fixed at a natural limit around 122 years. However, there is no fixed limit in animals. In animals, anti-aging interventions (dietary restrictions, rapamycin, genetic manipulations) postpone age-related diseases and thus automatically extend maximum lifespan. In humans, anti-aging interventions have not been yet implemented. Instead, by treating individual diseases, medical interventions allow a patient to live longer (despite morbidity), expanding morbidity span. In contrast, slowly aging individuals (centenarians) enter very old age in good health, but, when diseases finally develop, they do not receive thorough medical care and die fast. Although the oldest old die from age-related diseases, death certificates often list "old age", meaning that diseases were not even diagnosed and even less treated. The concept of absolute compression of morbidity is misleading in humans (in truth, there is no other way to compress morbidity as by denying thorough medical care) and false in animals (in truth, anti-aging interventions do not condense morbidity, they postpone it). Anti-aging interventions such as rapamycin may potentially extend both healthspan and maximal lifespan in humans. Combining anti-aging medicine with cutting-edge medical care, regardless of chronological age, will extend maximal lifespan further.

[This corrects the article DOI: 10.18632/oncoscience.395.].

The therapeutic landscape of cancer treatments is quickly evolving thanks to the advent of precision oncology. Discovery of novel druggable targets and more reliable biomarkers is a primary objective towards personalized strategies of cancer treatment. Highly expressed in the prostate epithelium within the human body, Transient Receptor Potential subfamily M member 8 (TRPM8) levels rise in primary and hormone naïve metastatic prostate cancer (PCa) lesions, which makes this channel an interesting prototype of molecular target. Recently, by combining a multidisciplinary approach to an in vitro genetic platform, we demonstrated that the combination of potent TRPM8 agonists with X-rays induces a massive apoptotic response in radioresistant pre-malignant and malignant models of primary prostate lesions. As well, TRPM8 activation enhances the efficacy of docetaxel or enzalutamide in eradicating hormone naïve metastatic PCa cells. Overall, our findings provide a solid rationale for pursuing the pre-clinical and clinical study of TRPM8 as a valuable target for future approaches of precise oncology in PCa.

The last decade has seen a continued escalation in rates of human papillomavirus related oropharyngeal malignancy (HPV-OPC). This has occurred despite established national vaccination programs. In contrast, HPV associated cervical cancer incidence rates have declined, due in part to effective cervical cancer screening programs, many of which have moved towards the detection of high-risk HPV (hrHPV) as an early marker of malignant potential. This raises questions as to whether similar hrHPV screening methods could be used for early detection of HPV-OPC. Persistent oral hrHPV is a prerequisite for the development of HPV-OPC and can be accurately detected in saliva. Despite this, single point saliva testing for hrHPV lacks sufficient sensitivity and specificity to allow for effective population screening. Recent published literature suggests the use of serial saliva testing in targeted high-risk individuals, with an emphasis on biomarker persistence and intensity patterns, as a potential means of detecting even subclinical microscopic disease. When coupled with serological testing, this has the potential to provide an accurate test for screening at risk individuals. Despite these promising developments, several significant barriers to an effective targeted screening program remain.

Inactivation of the tumor suppressor p53 has been generally accepted as a hallmark of tumor. MDM2 and MDMX, the two closely related proteins are considered to be critical for negatively regulating p53 activity through inhibitory binding to and post-translational modification of the p53 protein. We have demonstrated that MDMX facilitates MDM2-mediated p53 ubiquitination and degradation via recruitment of the ubiquitin-conjugating enzyme UbcH5c to the MDM2-MDMX heterooligomers. Here, we discuss our new findings from genetically engineered mouse models and a potential therapeutic strategy.

Conventional suspension cultures have been used in Acute Myeloid Leukemia (AML) research to study its biology as well as to screen any drug molecules, since its inception. Co-culture models of AML cells and other stromal cells as well as 3 dimensional (3D) culture models have gained much attention recently. These culture models try to recapitulate the tumour microenvironment and are found to be more suitable than suspension cultures. Though animal models are being used, they require more time, effort and facilities and hence, it is essential to develop cell culture models for high-throughput screening of drugs. Here, we discuss a new co-culture model developed by our research group involving acute myeloid leukemia (AML) cells and stimulated macrophages. Other studies on co-culture systems and relevance of 3D culture in leukemic research in understanding the pathology and treatment of leukemia are also reviewed.