Table of Contents

Volume 13, Issue 7

  May 2012

  Pages 451 - 584

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REVIEWS

Cyclin dependent kinases in cancer: Potential for therapeutic intervention

Miriam Canavese, Loredana Santo and Noopur Raje
Pages 451 - 457
http://dx.doi.org/10.4161/cbt.19589
Abstract | Full Text | PDF

Cell cycle progression through each phase is regulated by heterodimers formed by cyclin-dependent kinases (CDKs) and their regulatory partner proteins, the cyclins. Together they coordinate the cellular events through cell cycle. De-regulation of cell-cycle control due to aberrant CDK activity is a common feature of most cancer types.

Intensive research on small molecules that target cell cycle regulatory proteins has led to the identification of many candidate inhibitors that are able to arrest proliferation and induce apoptosis in neoplastic cells as a promising strategy to treat cancer. Interestingly, cyclin-dependent kinases (CDKs) have also been proposed as therapeutic targets for Multiple Myeloma (MM). Overexpression and aberrant expression of the cyclins, specifically the D cyclins is seen in the majority of MM underscoring the value of exploring CDK inhibition in MM which currently remains an incurable neoplastic plasma-cell disorder. It is characterized by clonal proliferation of malignant plasma cells in the bone marrow microenviroment and associated organ dysfunction. Recent preclinical and early clinical data explore several CDK inhibitors in the context of MM.

This review will provide an overview of the main classes of CDK inhibitors with a focus on their mechanism of action and discuss clinical and pharmacological implications of CDK inhibitors as possible therapeutic approaches for the treatment of cancer with specific consideration to MM.

Sensitization of (colon) cancer cells to death receptor related therapies: A report from the FP6-ONCODEATH research consortium

Alexander Pintzas, Boris Zhivotovsky, Spiros Linardopoulos, Jean-Claude Martinou, Juan Carlos Lacal, Sylvie Robine, George Nasioulas and Ladislav Andera
Pages 458 - 466
http://dx.doi.org/10.4161/cbt.19600
Abstract | Full Text | PDF

The objective of the ONCODEATH consortium [EU Research Consortium “ONCODEATH” (2006–2010)] was to achieve sensitization of solid tumor cells to death receptor related therapies using rational mechanism-based drug combinations of targeted therapies. In this collaborative effort, during a period of 42 mo, cell and animal model systems of defined oncogenes were generated. Exploitation of generated knowledge and tools enabled the consortium to achieve the following research objectives: (1) elucidation of tumor components which confer sensitivity or resistance to TRAIL-induced cell death; (2) providing detailed knowledge on how small molecule Hsp90, Aurora, Choline kinase, BRAF inhibitors, DNA damaging agents, HDAC and DNMT inhibitors affect the intrinsic apoptotic amplification and execution machineries; (3) optimization of combined action of TRAIL with these therapeutics for optimum effects with minimum concentrations and toxicity in vivo. These findings provide mechanistic basis for a pharmacogenomic approach, which could be exploited further therapeutically, in order to reach novel personalized therapies for cancer patients.




CLINICAL STUDY

Serum calcium, tumor size, and hormone receptor status in women with untreated breast cancer

Sunn Sunn H. Thaw, Abe Sahmoun and Gary G. Schwartz
Pages 467 - 471
http://dx.doi.org/10.4161/cbt.19606
Abstract | Full Text | PDF

Elevated serum levels of calcium are frequently observed in advanced breast cancer, but data on serum calcium and breast cancer characteristics at the time of breast cancer diagnosis are limited. We conducted a cross-sectional study of 555 women with newly-diagnosed, untreated breast cancer in North Dakota. We examined the relationship between tumor size, serum calcium and other clinical characteristics of breast tumors, including age and hormone receptor status, using multiple linear regressions. Tumors that were estrogen receptor negative tended to be associated with higher serum calcium levels (p = 0.07). We observed a significant positive correlation between tumor volume and serum calcium levels (adjusted for patient age, body mass index, hormonal receptors, stage at diagnosis, and grade). The association between tumor volume and serum calcium was limited to post-menopausal women. Our finding that postmenopausal women with larger breast tumors had significantly higher serum calcium levels is consistent with a calciotropic effect of early breast cancer in postmenopausal women.




BEDSIDE-TO-BENCH REPORT

Activity of pegylated liposomal doxorubicin in combination with gemcitabine in triple negative breast cancer with skin involvement: Two case reports

Tindara Franchina, Barbara Adamo, Giuseppina R.R. Ricciardi, Nicola Caristi, Rita Maria Agostino, Claudia Proto and Vincenzo Adamo
Pages 472 - 476
http://dx.doi.org/10.4161/cbt.19593
Abstract | Full Text | PDF

Breast carcinoma (BC) is a heterogeneous disease in terms of histology, therapeutic response, dissemination patterns to distant sites and patient outcomes. Triple-negative breast cancer (TNBC), defined by the lack of protein expression of estrogen and progesterone receptors and the absence of HER2 protein overexpression (ER–/PR–/HER2–) has significant clinical implications due to their poor prognosis and the lack of targeted agents. Skin involvement is one of the most distressing presentations of locally recurrent breast cancer and few studies have identified effective agents in this setting. In fact, the increasing use of anthracycline/taxane-based chemotherapy in the neoadjuvant and/or adjuvant settings has led to investigate new cytotoxic therapies such as the combination of pegylated liposomal doxorubicin (PLD) with gemcitabine. Here, we report two cases of disseminated TNBC with extensive cutaneous metastases and a remarkable response to PLD in combination with gemcitabine. Further investigations are needed to confirm the efficacy of this regimen in skin involvement and TNBC.




RESEARCH PAPERS

p63 expression correlates with sensitivity to the Eg5 inhibitor ZD4877 in bladder cancer cells

Lauren Marquis, Mai Tran, Woonyoung Choi, I-Ling Lee, Dennis Huszar, Arlene Siefker-Radtke, Colin Dinney and David J. McConkey
Pages 477 - 486
http://dx.doi.org/10.4161/cbt.19590
Abstract | Full Text | PDF

Antimitotics such as taxanes are being considered as alternatives to conventional cisplatin-based chemotherapy in patients with bladder cancer, but the molecular determinants of sensitivity or resistance to these agents in bladder cancer cells have not been defined. Here we examined the cytotoxic effects of a novel antimitotic, the Eg5 inhibitor AZD4877, in a molecularly diverse panel of human bladder cancer cell lines. The cells displayed heterogeneous responses to the drug that correlated closely with sensitivity to docetaxel but not with sensitivity to cisplatin. Global gene expression profiling identified p63 as the top gene that was differentially expressed between sensitive and resistant cell lines. Stable knockdown of p63 inhibited cell death induced by either AZD4877 or docetaxel and was associated with decreased proliferation and decreased expression of c-myc. Furthermore, c-myc knockdown also rendered cells resistant to AZD4877 or docetaxel. Together, our results implicate p63 and its downstream target c-myc as determinants of sensitivity to anti-mitotics in bladder cancer cells. Our data also suggest that anti-mitotics and cisplatin target different subsets of bladder cancer cells, a conclusion that may have important implications for the therapy of muscle-invasive bladder cancers.

Hedgehog signaling in glioblastoma multiforme

Stefanie Braun, Henry Oppermann, Antje Mueller, Christof Renner, Amalya Hovhannisyan, Rainer Baran-Schmidt, Rolf Gebhardt, Alan Hipkiss, Joachim Thiery, Jürgen Meixensberger and Frank Gaunitz
Pages 487 - 495
http://dx.doi.org/10.4161/cbt.19591
Abstract | Full Text | PDF

Glioblastoma multiforme (GBM) is the most malignant brain tumor in adults with a median survival of 14.6 mo under the best available treatment. New treatment strategies are therefore urgently required, for which a profound understanding of tumor biology is necessary. Much effort has been devoted to tumor-specific aberrant signaling processes. Recently it was discovered that the transcription factor Gli1, which is activated by hedgehog signaling, is a highly predictive marker in GBM, as determined by immunohistochemistry. To determine whether GBM cells have transcriptionally active Gli1, we performed experiments with reporter genes with cells isolated from surgically removed human tumors and cell lines. We also determined whether the hedgehog signaling inhibitor cyclopamine influences reporter gene expression and cell viability, and we determined the expression of Gli1, SHH and Patched1 by quantitative real-time RT-PCR. Reporter gene analysis of nine cultures and four cell lines demonstrated a significantly enhanced transcriptional activity in six tumor cell cultures and all cell lines. Analysis of cell viability in the presence of cyclopamine revealed a response of all cell cultures with the exception of one primary culture and one cell line, but only one cell line responded to cyclopamine with reduced hedgehog signaling activity. This indicates that the toxicity of cyclopamine toward GBM cells is independent from hedgehog signaling. Since no correlation between hedgehog activity and SHH, Gli1 and Patched1 mRNA levels was observed we conclude that other mechanisms aside from transcriptional regulation of these factors are responsible for hedgehog activity in tumor cells derived from GBM.

Open Access Article

Overexpression of IL-7 enhances cisplatin resistance in glioma

Lei Cui, Jun Fu, Jesse Chung-Sean Pang, Zhi-Kun Qiu, Xiao-Mei Liu, Fu-Rong Chen, Hong-Liu Shi, Ho-Keung Ng and Zhong-Ping Chen
Pages 496 - 503
http://dx.doi.org/10.4161/cbt.19592
Abstract | Full Text | PDF

Cisplatin is one of the most commonly used chemotherapeutic agents for glioma patients. In this study, array comparative genomic hybridization (aCGH) was used to identify genes associated with cisplatin resistance in a human glioma cell line. The cisplatin-resistant U251/CP2 cell line was derived by stepwise selection using cisplatin. The genetic aberrations of the U251 parental cell line and the U251/CP2 cells were analyzed using aCGH. RT-PCR was used to detect the expression of the altered genes revealed by aCGH. The sensitivity of glioma cells to cisplatin was determined by using the MTT assay. Apoptosis was detected using flow cytometry and western blot analysis. The IC₅₀ value of cisplatin in U251/CP2 cells was five times higher than its IC₅₀ in U251 cells. The U251 cells lost at least one copy each of the CFHR1 and CFHR3 genes, and both CFHR1 and CFHR3 were homozygously deleted in U251/CP2 cells. The U251/CP2 cells gained two to three copies of C8orf70 and IL-7 genes. IL-7 mRNA expression was studied in 12 glioma cell lines, and expression was positively correlated with the IC₅₀ of cisplatin. Furthermore, IL-7 mRNA expression was also positively correlated with the IC₅₀ of cisplatin in 91 clinical glioma specimens. Additionally, treatment with recombinant human IL-7 (rhIL-7) enhanced cisplatin resistance and increased the relative growth rate of the glioma cells. Moreover, the apoptosis induced by cisplatin could be inhibited by IL-7. In conclusion, our results suggest that IL-7 may play an important role in cisplatin resistance in glioma.

Ginsenoside Rg3 attenuates tumor angiogenesis via inhibiting bioactivities of endothelial progenitor cells

Jae-Won Kim, Seok-Yun Jung, Yi-Hong Kwon, Jun-Hee Lee, You Mie Lee, Boo-Yong Lee and Sang-Mo Kwon
Pages 504 - 515
http://dx.doi.org/10.4161/cbt.19599
Abstract | Full Text | PDF

Accumulating evidence suggests that Ginsenoside Rg3 appears to inhibit tumor growth including Lewis lung carcinoma, intestinal adenocarcinomas or B16 melanoma by inhibiting cell proliferation, tumor cell invasion and metastasis. Endothelial progenitor cells (EPCs) appear to play a key role in the growth of early tumors by intervening with the angiogenic switch promoting tumor neovessel formation by producing angiogenic cytokines during tumor progression. This paper reports a novel mechanism of Ginsenoside Rg3, a candidate anticancer bio-molecule, on tumor angiogenesis by inhibiting the multiple bioactivities of EPCs. When Ginsenoside Rg3 was applied to the ex vivo cultured outgrowth ECs, a type of EPCs, it inhibited the cell proliferation, cell migration and tubular formation of EPCs. Importantly, Ginsenoside Rg3 attenuated the phosphorylation cascade of the VEGF dependent p38/ERK signaling in vitro. The xenograft tumor model clearly showed that Ginsenoside Rg3 suppresses tumor growth and tumor angiogenesis by inhibiting the mobilization of EPCs from the bone marrow microenvironment to the peripheral circulation and modulates VEGF-dependent tumor angiogenesis. In conclusion, this study provides a potential therapeutic molecule, Ginsenoside Rg3, as an anticancer drug by inhibiting the EPC bioactivities.

Resveratrol sensitized leukemia stem cell-like KG-1a cells to cytokine-induced killer cells-mediated cytolysis through NKG2D ligands and TRAIL receptors

Liangshan Hu, Donglin Cao, Yuhua Li, Yanjie He and Kunyuan Guo
Pages 516 - 526
http://dx.doi.org/10.4161/cbt.19601
Abstract | Full Text | PDF

Human promyeloblastic leukemia KG-1a cells exhibit many characteristics similar to leukemia stem cells, which are resistant to chemotherapeutic drugs and hyposensitive to cytotoxic cells. Resveratrol (RES), as a member of plant polyphenols, has gained considerable attention due to its ability to prevent cancer from progressing. In this study, the potential of RES to sensitize KG-1a cells to cytolysis of cytokine-induced killer cells (CIKs) through NKG2D ligands and TNF-related apoptosis-inducing ligand (TRAIL) receptors were investigated. Twenty-five micromolars RES was found to inhibit approximately 50% of KG-1a cell growth and had the least growth-inhibition effect on peripheral blood mononuclear cells (PBMCs) after 24 h. Utilizing cytokines including interleukin-2 (IL-2) and interleukin-15 (IL-15) to activate PBMCs, we obtained substantial CD3⁺ CD56⁺ natural killer cell-like T lymphocytes that secreted cytokine interferon-γ (IFN-γ) and expressed NKG2D and TRAIL on their surfaces (i.e., cytokine-induced killer cells, CIKs). RES was shown to render KG-1a cells susceptible to CIK-mediated cytolysis estimated by LDH-release assay. This heightened sensitivity correlated with an increase in cell-surface expression of NKG2D ligands and death receptor 4 (DR4), coupled with a downregulation of cell-surface expression of decoy receptor 1 (DcR1) in KG-1a cells. Blocking NKG2D ligands or TRAIL with monoclonal antibodies could abrogate CIKs-mediated cytolysis. These results demonstrated that increased sensitivity of KG-1a cells, modulated by RES to alloreactive CIKs-mediated cytolysis is a phenomenon attributable to induced expression of NKG2D ligands and activation of TRAIL pathway. Thus, resveratrol combined with alloreactive CIKs merits clinical evaluation as a novel and effective immunotherapy strategy to eliminate residual leukemia stem cells.

Vasculogenic mimicry is a marker of poor prognosis in prostate cancer

Ranlu Liu, Kuo Yang, Chao Meng, Zhihong Zhang and Yong Xu
Pages 527 - 533
http://dx.doi.org/10.4161/cbt.19602
Abstract | Full Text | PDF

We investigated the role of vasculogenic mimicry (VM) in the progression of prostate cancer (PCa). Ninety-six patients who had undergone prostatectomy for treatment of PCa and for whom a complete record of clinical and follow-up data were available were reviewed. VM and matrix metalloproteinase-2 (MMP-2) were detected by immunohistochemical staining in frozen tissue sections. Relationship between VM and clinicopathological variables was analyzed statistically. Multivariate analyses were performed to assess the prognostic significance of VM. Results showed that out of the 96 PCa cases studied here, VM was detectable in 24 (25%) and was positively correlated with preoperative prostate-specific antigen (PSA) level, Gleason score, pathological stage, lymph node metastasis, seminal vesicle invasion, distant metastasis and PSA doubling time (PSADT). Univariate analysis showed that VM, PSA level, Gleason score, distant metastasis and PSADT were correlated with overall survival (OS), while VM, Gleason score, distant metastasis, local recurrence and PSADT were correlated with disease-free survival (DFS). Multivariable analysis indicated that the presence of VM, higher Gleason score and distant metastasis were the adverse predictors of OS and DFS. A higher widespread staining for MMP-2 was correlated with the VM-positive subgroup. In conclusion, VM mainly exists in the high risk PCa patients and is an independent marker of poor prognosis.

Sorafenib inhibits endogenous and IL-6/S1P induced JAK2-STAT3 signaling in human neuroblastoma, associated with growth suppression and apoptosis

Fan Yang, Veronica Jove, Ralf Buettner, Hong Xin, Jun Wu, Yan Wang, Sangkil Nam, Yibing Xu, Tasnim Ara, Yves A. DeClerck, Robert Seeger, Hua Yu and Richard Jove
Pages 534 - 541
http://dx.doi.org/10.4161/cbt.19603
Abstract | Full Text | PDF

Neuroblastoma is the most common extracranial solid tumor in the pediatric population. Sorafenib (Nexavar), a multikinase inhibitor, blocks cell proliferation and induces apoptosis in certain types of cancers. Here, we tested antitumor effects of sorafenib (≤ 10 µM) on four human neuroblastoma cell lines, CHLA255, CHLA171, CHLA90 and SK-N-AS. Sorafenib inhibited cell proliferation and induced apoptosis of neuroblastoma tumor cells in a dose-dependent manner. Sorafenib inhibited phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) proteins at Tyr705 in these cells, associated with inhibition of phosphorylated JAK2, an upstream kinase that mediates STAT3 phosphorylation. Expression of a constitutively-activated STAT3 mutant (pSTAT3-C) partially blocked the antitumor effects of sorafenib on neuroblastoma cells. Sorafenib also inhibited the phosphorylation of STAT3 induced by IL-6 and sphingosine-1-phosphate (S1P), a recently identified regulator for STAT3, in these tumor cells. Moreover, sorafenib downregulated phosphorylation of MAPK (p44/42) in neuroblastoma cells, consistent with inhibition of their upstream regulators MEK1/2. Sorafenib inhibited expression of cyclin E, cyclin D1/D2/D3, key regulators for cell cycle, and the antiapoptotic proteins Mcl-1 and survivin. Finally, sorafenib suppressed the growth of human neuroblastoma cells in a mouse xenograft model. Taken together, these findings suggest the potential use of sorafenib for the treatment of pediatric neuroblastomas.

Boswellic acid induces epigenetic alterations by modulating DNA methylation in colorectal cancer cells

Yan Shen, Masanobu Takahashi, Hyang-Min Byun, Alexander Link, Nupur Sharma, Francesc Balaguer, Hon-Chiu Leung, C. Richard Boland and Ajay Goel
Pages 542 - 552
http://dx.doi.org/10.4161/cbt.19604
Abstract | Full Text | PDF

Accumulating evidence suggests that chemopreventive effects of some dietary polyphenols may in part be mediated by their ability to influence epigenetic mechanisms in cancer cells. Boswellic acids, derived from the plant Boswellia serrata, have long been used for the treatment of various inflammatory diseases due to their potent anti-inflammatory activities. Recent preclinical studies have also suggested that this compound has anti-cancer potential against various malignancies. However, the precise molecular mechanisms underlying their anti-cancer effects remain elusive. Herein, we report that boswellic acids modulate DNA methylation status of several tumor suppressor genes in colorectal cancer (CRC) cells. We treated RKO, SW48 and SW480 CRC cell lines with the active principle present in boswellic acids, acetyl-keto-β-boswellic acid (AKBA). Using genome-wide DNA methylation and gene expression microarray analyses, we discovered that AKBA induced a modest genome-wide demethylation that permitted simultaneous re-activation of the corresponding tumor suppressor genes. The quantitative methylation-specific PCR and RT-PCR validated the gene demethylation and re-expression in several putative tumor suppressor genes including SAMD14 and SMPD3. Furthermore, AKBA inhibited DNMT activity in CRC cells. Taken together, these results lend further support to the growing notion that anti-cancer effect of boswellic acids may in part be due to its ability to demethylate and reactivate methylation-silenced tumor suppressor genes. These results suggest that not only boswellic acid might be a promising epigenetic modulator in the chemoprevention and treatment of CRC, but also provide a rationale for future investigations on the usefulness of such botanicals for epigenetic therapy in other human malignancies.

P53 and the proteasome regulate androgen receptor activity

Natalya V. Guseva, Oskar W. Rokhlin, Rebecca A. Glover and Michael B. Cohen
Pages 553 - 558
http://dx.doi.org/10.4161/cbt.19605
Abstract | Full Text | PDF

Mutual regulation of expression between p53 and AR has been reported. To further investigate the role of p53 in the regulation of AR expression, an ARE-Luciferase vector was inserted into LNCaP and into LNCaP-sip53 transfectants, and AR activity was quantitatively estimated after treatment with proteasome inhibitors. LNCaP expresses a mutated form of AR. Therefore, to investigate whether p53 can modulate the expression of wild-type (wt) of AR, we transfected PC3-wtAR with a p53 vector together with ARE-Luc and showed that p53 expression decreased DHT-dependent activity of wtAR. Since proteasomes also participate in AR transcriptional activity, we investigated the role of p53 in proteasome-dependent inhibition of AR activity. More than 80% of AR activity was inhibited by 3 μM of lactacystin in LNCaP whereas no inhibition was noted in LN-sip53. We also found that lactacystin decreased AR-DNA binding 3-fold in LNCaP but no binding decrease was observed in LN-sip53. Taken together, our data show that the inhibitory effects of proteasome inhibitors are dependent on p53 status, at least in prostate cancer. Therefore, the role of p53 during treatment with proteasome inhibitors in different tumors should be further investigated.

Antitumor effects of novel shorter truncated insulin-like growth factor I receptors

Yojiro Ojima, Atsushi Hongo, Yixuan Liu, Lisha Zhu, Tomoyuki Kusumoto, Keiichiro Nakamura, Noriko Seki and Yuji Hiramatsu
Pages 559 - 566
http://dx.doi.org/10.4161/cbt.19609
Abstract | Full Text | PDF

We generated novel truncated insulin-like growth factor I receptors (IGF-IRs) designated as 126/STOP, 223/STOP and 325/STOP in order to establish shorter soluble IGF-IRs than previously reported 486/STOP without abrogating the same antitumor effects. Stable transfection of 223/STOP and 325/STOP, but not 126/STOP caused inhibition of anchorage-independent growth of CaOV-3 ovarian cancer cells in vitro. This antitumor effect was reproduced when we used recombinant proteins of these constructs, suggesting a bystander effect of these shorter truncated IGF-IRs. Tumorigenesis in vivo of CaOV-3 cells tranfected with 223/STOP or 325/STOP was strictly inhibited, and inoculation of these cells in nude mice caused massive apoptosis exclusively in vivo. Phosphorylations of IGF-IR and Akt, but not Erk were attenuated in 223/STOP- or 325/STOP-transfected CaOV-3 cells, and downregulations of IGF-IR and Akt phosphorylation seemed to play at least a partial role in the anti-tumor effect of these novel truncated IGF-IRs. Since 223/STOP and 325/STOP are smaller in size than previously reported 486/STOP, and they retain the same antitumor effects, they could be good candidates for clinical application in the future.

Sorafenib and HDAC inhibitors synergize to kill CNS tumor cells

Yong Tang, Adly Yacoub, Hossein A. Hamed, Andrew Poklepovic, Gary Tye, Steven Grant and Paul Dent
Pages 567 - 574
http://dx.doi.org/10.4161/cbt.19771
Abstract | Full Text | PDF

The present studies were designed to determine whether the multi-kinase inhibitor sorafenib (Nexavar) interacted with histone deacetylase inhibitors to kill glioblastoma and medulloblastoma cells. In a dose-dependent fashion sorafenib lethality was enhanced in multiple genetically disparate primary human glioblastoma isolates by the HDAC inhibitor sodium valproate (Depakote). Drug exposure reduced phosphorylation of p70 S6K and of mTOR. Similar data to that with valproate were also obtained using the HDAC inhibitor vorinostat (Zolinza). Sorafenib and valproate also interacted to kill medulloblastoma and PNET cell lines. Treatment with sorafenib and HDAC inhibitors radio-sensitized both GBM and medulloblastoma cell lines. Knock down of death receptor (CD95) expression protected GBM cells from the drug combination, as did overexpression of c-FLIP-s, BCL-XL and dominant negative caspase 9. Knock down of PDGFRα recapitulated the effect of sorafenib in combination with HDAC inhibitors. Collectively, our data demonstrate that the combination of sorafenib and HDAC inhibitors kills through activation of the extrinsic pathway, and could represent a useful approach to treat CNS-derived tumors.

The chemopreventive and clinically used agent curcumin sensitizes HPV^- but not HPV⁺ HNSCC to ionizing radiation, in vitro and in a mouse orthotopic model

Stephen Tuttle, Lauren Hertan, Natalie Daurio, Sarah Porter, Charanya Kaushick, Daqing Li, Shunsuke Myamoto, Alex Lin, Bert W. O’Malley and Constantinos Koumenis
Pages 575 - 584
http://dx.doi.org/10.4161/cbt.19772
Abstract | Full Text | PDF

Radiation therapy (RT) plays a critical role in the local-regional control of head and neck squamous cell carcinoma (HNSCC). However, the efficacy of RT in treating HNSCC is limited by severe normal tissue toxicity, predominantly mucositis. One pharmacological approach for increasing the clinical response to RT is the use of radiation response modifiers that preferentially sensitize tumor cells. Previously we demonstrated that curcumin, a natural plant polyphenol, increased the radiation sensitivity of HNSCC cells and that the observed sensitization was dependent on curcumin-mediated inhibition of thioredoxin reductase 1 (TxnRd1) a key cytosolic regulator of redox-dependent signaling. Here, we examined curcumin-induced radiation sensitization in HNSCC cell lines with differing HPV status and expressing different levels of TxnRd1, in vitro. The intrinsic radiation resistance of the HPV^- cell lines was significantly higher than the HPV⁺ cell lines used in our study. Notably, all of the HPV^- cell lines expressed high levels of TxnRd1 and exhibited higher intrinsic resistance to RT. While curcumin was effective at increasing the radiation response of the resistant HPV^- cell lines it had no effect on the HPV⁺ cells. Based on these findings we employed an orthotopic, HPV^- HNSCC tumor model in athymic nude mice to examine the effect of combining curcumin with fractionated RT, in vivo. The combination of curcumin feeding and fractionated RT had a significant effect on tumor doubling time and overall animal survival. We therefore propose that curcumin and RT should be considered as a first line treatment of HPV^- HNSCC.