The emerging roles and therapeutic potential of cyclin-dependent kinase 11 (CDK11) in human cancer.

Overexpression and/or hyperactivation of cyclin-dependent kinases (CDKs) are common features of most cancer types. CDKs have been shown to play important roles in tumor cell proliferation and growth by controlling cell cycle, transcription, and RNA splicing. CDK4/6 inhibitor palbociclib has been recently approved by the FDA for the treatment of breast cancer. CDK11 is a serine/threonine protein kinase in the CDK family and recent studies have shown that CDK11 also plays critical roles in cancer cell growth and proliferation. A variety of genetic and epigenetic events may cause universal overexpression of CDK11 in human cancers. Inhibition of CDK11 has been shown to lead to cancer cell death and apoptosis. Significant evidence has suggested that CDK11 may be a novel and promising therapeutic target for the treatment of cancers. This review will focus on the emerging roles of CDK11 in human cancers, and provide a proof-of-principle for continued efforts toward targeting CDK11 for effective cancer treatment

Radial free forearm flap versus pectoralis major pedicled flap for reconstruction in patients with tongue cancer : assessment of quality of life

This study investigated the quality of life of Chinese patients with tongue cancer who had undergone immediate flap reconstruction surgery. In addition, we compared 2 groups of patients: those who had received radial forearm free flap (RFFF) surgery and others who had received pectoralis major myocutaneous flap (PMMF) surgery. Patients who received RFFF or PMMF reconstruction after primary tongue cancer treated with total and subtotal tongue resection were eligible for the current study. The patients? demographic data, medical history, and quality of life scores (14-item Oral Health Impact Profile (OHIP-14) and the University of Washington Quality of Life (UW-QOL) questionnaires) were collected. A total of 41 of 63 questionnaires were returned (65.08%). There were significant differences between the 2 groups in the gender (p< .05). Patients reconstructed with RFFF performed better in the shoulder domains, in addition to worse appearance domains. Using either RFFF or PMMF for reconstruction of defects after tongue cancer resection significantly influences a patient?s quality of life. Data from this study provide useful information for physicians and patients during their discussion of reconstruction modalities for tongue cancers

Therapeutic microparticles functionalized with biomimetic cardiac stem cell membranes and secretome

Stem cell therapy represents a promising strategy in regenerative medicine. However, cells need to be carefully preserved and processed before usage. In addition, cell transplantation carries immunogenicity and/or tumourigenicity risks. Mounting lines of evidence indicate that stem cells exert their beneficial effects mainly through secretion (of regenerative factors) and membrane-based cell–cell interaction with the injured cells. Here, we fabricate a synthetic cell-mimicking microparticle (CMMP) that recapitulates stem cell functions in tissue repair. CMMPs carry similar secreted proteins and membranes as genuine cardiac stem cells do. In a mouse model of myocardial infarction, injection of CMMPs leads to the preservation of viable myocardium and augmentation of cardiac functions similar to cardiac stem cell therapy. CMMPs (derived from human cells) do not stimulate T-cell infiltration in immuno-competent mice. In conclusion, CMMPs act as ‘synthetic stem cells’ which mimic the paracrine and biointerfacing activities of natural stem cells in therapeutic cardiac regeneration

Novel strategies to prevent the development of multidrug resistance (MDR) in cancer

The development of multidrug resistance (MDR) is one of the major challenges to the success of traditional chemotherapy treatment in cancer patients. Most studies to date have focused on strategies to reverse MDR following its development. However, agents utilizing this approach have proven to be of limited clinical use, failing to demonstrate an improvement in therapeutic efficacy with almost no significant survival benefits observed in cancer clinical trials. An alternative approach that has been applied is to prevent or delay MDR prior or early in its development. Recent investigations have shown that preventing the emergence of MDR at the onset of chemotherapy treatment, rather than reversing MDR once it has developed, may assist in overcoming drug resistance. In this review, we focus on a number of novel strategies used by small-molecule inhibitors to prevent the development of MDR. These agents hold great promise for prolonging the efficacy of chemotherapy treatment and improving the clinical outcomes of patients with cancers that are susceptible to MDR development

Regulation of microRNAs function by circular RNAs in human cancer.

Circular RNAs (circRNAs) are a newly validated class of endogenous non-coding RNA, generated from the ligation of exons, introns, or both, which arise via a diverse number of cellular mechanisms. Due to rapid advances in the development of combined high-throughput sequencing and bioinformatics analyzing tools, many circRNAs have recently been discovered, revealing an expansive number of ubiquitously expressed mammalian circRNAs. Interestingly, it has recently been confirmed that circRNAs bind to microRNAs (miRs), as miR "sponges", acting to suppress miR function. As miRs are known to alter the development and progression of cancer, circRNAs may offer a novel diagnostic and prognostic biomarker for cancer. Indeed, recent evidence has shown that circRNAs are associated with many human cancers. Herein, we review the molecular characteristics and biogenesis of circRNAs, with a focus on newly identified circRNAs that may play an important role in human cancer, through their regulation of miR expression

The emerging roles and therapeutic potential of cyclin-dependent kinase 11 (CDK11) in human cancer.

Overexpression and/or hyperactivation of cyclin-dependent kinases (CDKs) are common features of most cancer types. CDKs have been shown to play important roles in tumor cell proliferation and growth by controlling cell cycle, transcription, and RNA splicing. CDK4/6 inhibitor palbociclib has been recently approved by the FDA for the treatment of breast cancer. CDK11 is a serine/threonine protein kinase in the CDK family and recent studies have shown that CDK11 also plays critical roles in cancer cell growth and proliferation. A variety of genetic and epigenetic events may cause universal overexpression of CDK11 in human cancers. Inhibition of CDK11 has been shown to lead to cancer cell death and apoptosis. Significant evidence has suggested that CDK11 may be a novel and promising therapeutic target for the treatment of cancers. This review will focus on the emerging roles of CDK11 in human cancers, and provide a proof-of-principle for continued efforts toward targeting CDK11 for effective cancer treatment

Novel mechanisms and approaches to overcome multidrug resistance in the treatment of ovarian cancer

Ovarian cancer remains the leading cause of gynecological cancer-related mortality despite the advances in surgical techniques and chemotherapy drugs over the past three decades. Multidrug resistance (MDR) to chemotherapy is the major cause of treatment failure. Previous research has focused mainly on strategies to reverse MDR by targeting the MDR1 gene encoded P-glycoprotein (Pgp) with small molecular compound inhibitors. However, prior Pgp inhibitors have shown very limited clinical success because these agents have relatively low potency and high toxicity. Therefore, identification of more specific and potent new inhibitors would be useful. In addition, emerging evidence suggests that cancer stem cells (CSCs), deregulated non-coding RNA (ncRNA), autophagy, and tumor heterogeneity also contribute significantly to drug sensitivity/resistance in ovarian cancer. This review summarizes these novel mechanisms of MDR and evaluates several new concepts to overcome MDR in the treatment of ovarian cancer. These new strategies include overcoming MDR with more potent and specific Pgp inhibitors, targeting CSCs and ncRNA, modulating autophagy signaling pathway, and targeting tumor heterogeneity. (C) 2016 Elsevier B.V. All rights reserved

Aberrant CDK9 expression within chordoma tissues and the therapeutic potential of a selective CDK9 inhibitor LDC000067

Objectives: Chordomas are slow-growing malignancies that commonly affect vital neurological structures. These neoplasms are highly resistant to current chemotherapeutic regimens and often recur after surgical intervention. Therefore, there is an urgent need to identify molecular targets and more robust drugs to improve chordoma patient outcomes. It is well accepted that cyclin-dependent protein kinase 9 (CDK9) has tumorigenic roles in various cancers; however, the expression and significance of CDK9 in chordoma remains unknown. Methods: Expression of CDK9 in chordoma cell lines and tumor tissues was examined by Western blot and immunohistochemistry (IHC). The correlation between CDK9 expression in patient tissues and clinical prognosis was analyzed. The functional roles of CDK9 in chordoma were investigated after the addition of small interfering RNA (siRNA) and CDK9 inhibitor (LDC000067). Cell growth and proliferation were assessed with MTT and clonogenic assays. The effect of CDK9 inhibition on chordoma cells was further evaluated with a three-dimensional (3D) cell culture model which mimics the in vivo environment. Results: CDK9 was expressed in both chordoma cell lines and chordoma tissues. High- expression of CDK9 correlated with recurrence and poor outcomes for chordoma patients. CDK9 silencing with siRNA decreased growth and proliferation of chordoma cells and lowered levels of Mcl-1 and RNA polymerase II (RNAP II) phosphorylation. Pharmacological inhibition of CDK9 with the small molecular inhibitor LDC000067 reduced cell growth, supported apoptosis, suppressed cell colony formation in a clonogenic assay, and decreased spheroid growth in 3D culture. Conclusion: We demonstrate that CDK9 expression in chordoma correlates with patient outcome, and, when inhibited, chordoma cell growth and proliferation significantly decreases. Taken together, these results support CDK9 as an emerging potential target in chordoma therapy

Regulation of microRNAs function by circular RNAs in human cancer

Circular RNAs (circRNAs) are a newly validated class of endogenous non-coding RNA, generated from the ligation of exons, introns, or both, which arise via a diverse number of cellular mechanisms. Due to rapid advances in the development of combined high-throughput sequencing and bioinformatics analyzing tools, many circRNAs have recently been discovered, revealing an expansive number of ubiquitously expressed mammalian circRNAs. Interestingly, it has recently been confirmed that circRNAs bind to microRNAs (miRs), as miR “sponges”, acting to suppress miR function. As miRs are known to alter the development and progression of cancer, circRNAs may offer a novel diagnostic and prognostic biomarker for cancer. Indeed, recent evidence has shown that circRNAs are associated with many human cancers. Herein, we review the molecular characteristics and biogenesis of circRNAs, with a focus on newly identified circRNAs that may play an important role in human cancer, through their regulation of miR expression