Curcumin: A review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma

Curcumin (diferuloylmethane) is a polyphenol derived from the Curcuma longa plant, commonly known as turmeric. Curcumin has been used extensively in Ayurvedic medicine for centuries, as it is nontoxic and has a variety of therapeutic properties including anti-oxidant, analgesic, anti-inflammatory and antiseptic activity. More recently curcumin has been found to possess anti-cancer activities via its effect on a variety of biological pathways involved in mutagenesis, oncogene expression, cell cycle regulation, apoptosis, tumorigenesis and metastasis. Curcumin has shown anti-proliferative effect in multiple cancers, and is an inhibitor of the transcription factor NF-κB and downstream gene products (including c-myc, Bcl-2, COX-2, NOS, Cyclin D1, TNF-α, interleukins and MMP-9). In addition, curcumin affects a variety of growth factor receptors and cell adhesion molecules involved in tumor growth, angiogenesis and metastasis. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and treatment protocols include disfiguring surgery, platinum-based chemotherapy and radiation, all of which may result in tremendous patient morbidity. As a result, there is significant interest in developing adjuvant chemotherapies to augment currently available treatment protocols, which may allow decreased side effects and toxicity without compromising therapeutic efficacy. Curcumin is one such potential candidate, and this review presents an overview of the current in vitro and in vivo data supporting its therapeutic activity in head and neck cancer as well as some of the challenges concerning its development as an adjuvant chemotherapeutic agent

A DNA-binding Molecule Targeting the Adaptive Hypoxic Response in Multiple Myeloma has Potent Anti-tumor Activity

Multiple myeloma is incurable and invariably becomes resistant to chemotherapy. Although the mechanisms remain unclear, hypoxic conditions in the bone marrow have been implicated in contributing to multiple myeloma progression, angiogenesis, and resistance to chemotherapy. These effects occur via adaptive cellular responses mediated by hypoxia-inducible transcription factors (HIF), and targeting HIFs can have anticancer effects in both solid and hematologic malignancies. Here, it was found that in most myeloma cell lines tested, HIF1α, but not HIF2α expression was oxygen dependent, and this could be explained by the differential expression of the regulatory prolyl hydroxylase isoforms. The anti–multiple myeloma effects of a sequence-specific DNA-binding pyrrole-imidazole (Py-Im) polyamide (HIF-PA), which disrupts the HIF heterodimer from binding to its cognate DNA sequences, were also investigated. HIF-PA is cell permeable, localizes to the nuclei, and binds specific regions of DNA with an affinity comparable with that of HIFs. Most of the multiple myeloma cells were resistant to hypoxia-mediated apoptosis, and HIF-PA treatment could overcome this resistance in vitro. Using xenograft models, it was determined that HIF-PA significantly decreased tumor volume and increased hypoxic and apoptotic regions within solid tumor nodules and the growth of myeloma cells engrafted in the bone marrow. This provides a rationale for targeting the adaptive cellular hypoxic response of the O_2-dependent activation of HIFα using polyamides

The Malignant Pleural Effusion as a Model to Investigate Intratumoral Heterogeneity in Lung Cancer

Malignant Pleural Effusions (MPE) may be useful as a model to study hierarchical progression of cancer and/or intratumoral heterogeneity. To strengthen the rationale for developing the MPE-model for these purposes, we set out to find evidence for the presence of cancer stem cells (CSC) in MPE and demonstrate an ability to sustain intratumoral heterogeneity in MPE-primary cultures. Our studies show that candidate lung CSC-expression signatures (PTEN, OCT4, hTERT, Bmi1, EZH2 and SUZ12) are evident in cell pellets isolated from MPE, and MPE-cytopathology also labels candidate-CSC (CD44, cMET, MDR-1, ALDH) subpopulations. Moreover, in primary cultures that use MPE as the source of both tumor cells and the tumor microenvironment (TME), candidate CSC are maintained over time. This allows us to live-sort candidate CSC-fractions from the MPE-tumor mix on the basis of surface markers (CD44, c-MET, uPAR, MDR-1) or differences in xenobiotic metabolism (ALDH). Thus, MPE-primary cultures provide an avenue to extract candidate CSC populations from individual (isogenic) MPE-tumors. This will allow us to test whether these cells can be discriminated in functional bioassays. Tumor heterogeneity in MPE-primary cultures is evidenced by variable immunolabeling, differences in colony-morphology, and differences in proliferation rates of cell subpopulations. Collectively, these data justify the ongoing development of the MPE-model for the investigation of intratumoral heterogeneity, tumor-TME interactions, and phenotypic validation of candidate lung CSC, in addition to providing direction for the pre-clinical development of rational therapeutics

Curcumin: A Review of Anti-Cancer Properties and Therapeutic Activity in Head & Neck Squamous Cell Carcinoma

Abstract Curcumin (diferuloylmethane) is a polyphenol derived from the Curcuma longa plant, commonly known as turmeric. Curcumin has been used extensively in Ayurvedic medicine for centuries, as it is nontoxic and has a variety of therapeutic properties including anti-oxidant, analgesic, anti-inflammatory and antiseptic activity. More recently curcumin has been found to possess anti-cancer activities via its effect on a variety of biological pathways involved in mutagenesis, oncogene expression, cell cycle regulation, apoptosis, tumorigenesis and metastasis. Curcumin has shown anti-proliferative effect in multiple cancers, and is an inhibitor of the transcription factor NF-κB and downstream gene products (including c-myc, Bcl-2, COX-2, NOS, Cyclin D1, TNF-α, interleukins and MMP-9). In addition, curcumin affects a variety of growth factor receptors and cell adhesion molecules involved in tumor growth, angiogenesis and metastasis. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and treatment protocols include disfiguring surgery, platinum-based chemotherapy and radiation, all of which may result in tremendous patient morbidity. As a result, there is significant interest in developing adjuvant chemotherapies to augment currently available treatment protocols, which may allow decreased side effects and toxicity without compromising therapeutic efficacy. Curcumin is one such potential candidate, and this review presents an overview of the current in vitro and in vivo data supporting its therapeutic activity in head and neck cancer as well as some of the challenges concerning its development as an adjuvant chemotherapeutic agent

Adipose-Derived Mesenchymal Stromal Cells Persist in Tissue-Engineered Vocal Fold Replacement in Rabbits.

Objectives:Cell therapies using mesenchymal stromal cells (MSCs) have been proposed as a promising new tool for the treatment of vocal fold scarring. However, the mechanisms by which MSCs promote healing as well as their duration of survival within the host vocal fold have yet to be defined. The aim of this work was to assess the persistence of embedded MSCs within a tissue-engineered vocal fold mucosal replacement in a rabbit model of vocal fold injury.Methods:Male rabbit adipose-derived MSCs were embedded within a 3-dimensional fibrin gel, forming the cell-based outer vocal fold replacement. Four female rabbits underwent unilateral resection of vocal fold epithelium and lamina propria and reconstruction with cell-based outer vocal fold replacement implantation. Polymerase chain reaction and fluorescent in situ hybridization for the sex-determining region of the Y chromosome (SRY-II) in the sex-mismatched donor-recipient pairs sought persistent cells after 4 weeks.Results:A subset of implanted male cells was detected in the implant site at 4 weeks. Many SRY-II-negative cells were also detected at the implant site, presumably representing native female cells that migrated to the area. No SRY-II signal was detected in contralateral control vocal folds.Conclusions:The emergent tissue after implantation of a tissue-engineered outer vocal fold replacement is derived both from initially embedded adipose-derived stromal cells and infiltrating native cells. Our results suggest this tissue-engineering approach can provide a well-integrated tissue graft with prolonged cell activity for repair of severe vocal fold scars

Targeting hypoxia-mediated gene transcription with a novel polyamide drug designed to disrupt the HIF1α/β heterodimer binding overcomes resistance to hypoxia in myeloma cell lines

Despite recent advancements in therapy, multiple myeloma (MM) remains incurable. While the reasons for this are unclear, it is felt that the bone marrow (BM) microenvironment may confer protective advantages to MM. The BM is known to be hypoxic compared to other tissues, and while oxygen stress can kill tumor cells, it is also known that hypoxia promotes tumor progression, metastasis, angiogenesis, and resistance to chemo- and radiation therapy. This suggests that hypoxic conditions in the BM may contribute to MM resistance, and therefore targeting the hypoxia response may be of therapeutic benefit. The adaptive response to hypoxia is mediated by a constitutively expressed β-subunit (HIF-1β), which forms a heterodimer with the inducible α-subunit (HIF-1α), although HIF-1α is frequently found to be constitutively expressed in some MM cell lines. In order to target the hypoxic response in MM, we blocked HIF-mediated gene transcription using a novel class of DNA-binding pyrrole-imidazole (Py-Im) polyamide (PA) drugs that are designed to target and disrupt the HIF1α/β heterodimer from binding to its cognate DNA sequence. Using a hypoxia chamber, we cultured MM cell lines (OPM-2, 8226, U266, MM1.S) under normoxia (22% O2, 5% CO2) or hypoxia (0.1% O2, 5% CO2) for 72 hours and assayed for apoptosis. We found that 8226 and U266 cell lines were relatively resistant to hypoxia-mediated apoptosis (∼15-20% apoptosis), but that OPM-2 was much more sensitive (>50% apoptosis), whilst MM1.S was intermediate in sensitivity (∼25% apoptosis). Using immunoblots, we found that cell lines with constitutive expression of HIF-1α were resistance to hypoxia, suggesting that constitutive HIF activity predicts MM resistance to hypoxia. We then tested whether treatment with our novel PA drug could overcome resistance to hypoxia-induced apoptosis. After confirming the ability of the PA inhibitor to specifically block HIF-mediated transcription using MM cells with a HIF-response element-reporter construct, as well as inhibition of VEGF mRNA expression, we next assayed the effect of PA (0.1-10 μM) treatment in MM cells as described above. PA was only mildly cytotoxic to MM cells under normoxia, but we observed a significant synergistic induction of apoptosis under hypoxic conditions. These effects were further potentiated when PA treatment was combined with rapamycin (0.1-100 nM). Our data suggests that the HIF-mediated hypoxic response plays an important role in MM sensitivity to hypoxia, likely through the induction of specific survival genes. In conclusion, our preliminary data shows that targeting the hypoxic response in MM with a specific polyamide drug that targets the HIF-response, alone or in combination with mTOR inhibitors, may provide an effective and novel treatment in the hypoxic BM microenvironment

Inactivation of the CYLD Deubiquitinase by HPV E6 Mediates Hypoxia-Induced NF-kappa B Activation

The biochemical mechanisms that underlie hypoxia-induced NF-kappa B activity have remained largely undefined. Here, we find that prolonged hypoxia-induced NF-kappa B activation is restricted to cancer cell lines infected with high-risk human papillomavirus (HPV) serotypes. The HPV-encoded E6 protein is necessary and sufficient for prolonged hypoxia-induced NF-kappa B activation in these systems. The molecular target of E6 in the NF-kappa B pathway is the CYLD lysine 63 (K63) deubiquitinase, a negative regulator of the NF-kappa B pathway. Specifically, hypoxia stimulates E6-mediated ubiquitination and proteasomal degradation of CYLD. Given the established role of NF-kappa B in human carcinogenesis, these findings provide a potential molecular/viral link between hypoxia and the adverse clinical outcomes observed in HPV-associated malignancies