Table of Contents

Volume 13, Issue 9

  July 2012

  Pages 701 - 830

View covers archive

 Issue Catalogue (MARC XML)

LETTER TO THE EDITOR

Dermatological manifestations of palifermin therapy: A common side effect of its use in oncology

Shailendra Kapoor
Page 701
http://dx.doi.org/10.4161/cbt.20566
Abstract | Full Text | PDF

I read with great interest the recent article by Yazbeck et al in a recent issue of your esteemed journal. The article provides for highly interesting reading. Palifermin clearly has a definite benefit in oncology. However, its clinical use may be associated with the development of a number of dermatological side effects. For instance, Kaloyannidis et al have reported the development of mucosal hyperpigmemtation accompanied by allodynia following the clinical use of palifermin. Similarly hyperkeratosis, hyperplastic gingivitis and macroglossia may occur secondary to palifermin administration. Palifermin use may also be associated with the development of lichenoid lesions that are primarily seen in the intertriginous areas. These lesions surprisingly stain positive with antibodies to Ki-67 and show histological features similar to verruca plana. Palifermin may also trigger over expression of filaggrin resulting in the development of flexural hyper pigmentation.




CLINICAL STUDY

Increased frequency of circulating invariant natural killer T cells in malignant pleural mesothelioma patients

Emanuela Altomare, Silvia Fallarini, Gabriele Biaggi, Elisabetta Gattoni, Mario Botta and Grazia Lombardi
Pages 702 - 711
http://dx.doi.org/10.4161/cbt.20553
Abstract | Full Text | PDF

Invariant natural killer T (iNKT) cells are a distinct subset of human T cells, which expresses an invariant T cell receptor Vα24 Jα18 and recognizes glycolipid antigens in the context of CD1d molecules. iNKT cells exert pivotal regulatory roles in many immune responses, including antitumor immune responses. Alterations in iNKT cell frequency, phenotype, and activation state have been reported in cancer patients. No data are available on the iNKT cells in malignant pleural mesothelioma (MPM), a rare, but very aggressive, malignancy of the pleura with a very poor prognosis. Here, we studied the frequency, phenotype, and cytokine profile of circulating iNKT cells in MPM patients, and correlated results with tumor histological types (epithelioid, sarcomatoid, biphasic) and clinical stages (I, II, III). We found that the iNKT cell frequency was significantly increased in MPM patients with epithelioid and sarcomatoid types in comparison with healthy volunteers (HV); only three biphasic mesotheliomas were available in this study, thus no conclusions can be drawn for this MPM type. The increased frequency significantly correlates with the clinical stage of tumor with the highest value at the stage III in both epithelioid and sarcomatoid subtypes. According to the histological types, we measured changes in the frequencies of CD4⁺CD8⁺ (DP) and CD4^-CD8^- (DN), but not in the cytokine profiles (IFN-γ/IL-4 expression). These results demonstrate that the frequency of iNKT cells is increased in MPM patients and that this increase correlates with MPM type and stage.




RESEARCH PAPERS

A feasibility study on gene therapy of pancreatic carcinoma with Ad-PUMA

Haijuan Wang, Wei Pei, Qingchun Luan, Fei Ma, Shaohua Zhou, zhilong zhao, Xiting Meng, Xueyan Zhang, Xiao Liang, Yan Chen, Qimin Zhan, Chen Lin, Haili Qian and Ping Zhao
Pages 712 - 719
http://dx.doi.org/10.4161/cbt.20552
Abstract | Full Text | PDF

Pancreatic cancer is one of the most malignant tumors with high mortality and poor prognosis even with the aggressive conventional therapies. Biotherapy based on the understanding of tumorigenesis mechanism is ongoing to improve the outcomes of cancer patients. We sought here to evaluate the therapeutic potential of a proapoptotic gene, PUMA, in pancreatic cancer. We found that PUMA was differently expressed in a series of pancreatic ductal adenocarcinoma cancer cell lines, and adenovirus-mediated expression of PUMA (Ad-PUMA) in these cells resulted in massive apoptosis. PUMA was more potent than p53 in suppressing growth of cancer cells. RT-PCR and Western Blot revealed that exogenous PUMA was expressed 6 h after Ad-PUMA infection. Furthermore, we assessed the efficacy of Ad-PUMA combining anticancer drugs (5-fluorouracil, cisplatin, gemcitabine hydrochloride, respectively) in these pancreatic cancer cell lines. Data revealed that PUMA significantly sensitized pancreatic carcinoma cell lines to chemotherapeutics, which may be resulted from abundant apoptosis induction. In nude mice with PANC-1 xenografts, Ad-PUMA treatment significantly inhibited the tumor growth. These results suggest that PUMA is a potent molecular tool in suppressing tumor growth sensitizing pancreatic carcinoma cells to chemical drugs. PUMA plays roles in negatively regulating cancer cell growth and may be a promising tool for cancer biotherapy, with or without combination with chemotherapeutic agents.

HIF1A C1772T polymorphism leads to HIF-1α mRNA overexpression in prostate cancer patients

Michael Vainrib, Maya Golan, Sharon Amir, Duyen T. Dang, Long H. Dang, Anat Bar-Shira, Avi Orr-Urtreger, Haim Matzkin and Nicola J. Mabjeesh
Pages 720 - 726
http://dx.doi.org/10.4161/cbt.20554
Abstract | Full Text | PDF

Hypoxia-inducible factor 1α (HIF-1α) gene polymorphisms have been investigated for a possible role in mediating genetic predisposition to cancer. Our previous data show that men homozygous to C1772T polymorphism had 4-fold risk to develop prostate cancer. Therefore, we studied the effects of C1772T polymorphism on HIF-1α expression. HIF-1α mRNA expression levels were significantly higher in peripheral blood leukocytes of prostate cancer patients with the TT genotype compared with the CC genotype. Expression of C1772T HIF-1α in HIF-1α knockout cancer cells showed higher expression levels and stabilization of HIF-1α mRNA compared with the wild-type. Mutated HIF-1α protein half-life was similar to that of the wild-type. Hence, our data provide evidence that C1772T polymorphism causes activation of HIF-1α as a gain-of-function mechanism driven by stabilization of HIF-1α mRNA. These findings may also explain the increased risk of men homozygous to this mutation to develop prostate cancer.

HMGB1 was a pivotal synergistic effecor for CpG oligonucleotide to enhance the progression of human lung cancer cells

Chunhong Wang, Guangru Fei, Zhongmin Liu, Qinchuan Li, Zengguang Xu and Tao Ren
Pages 727 - 736
http://dx.doi.org/10.4161/cbt.20555
Abstract | Full Text | PDF

High-mobility group box 1 (HMGB1) has been implicated in a variety of biologically important processes, including transcription, DNA repair, differentiation, development, and extracellular signaling. However, the potential role of HMGB1 in tumor biology still remains intractable. Our previous study showed that TLR9 response to CpG oligonucleotide (ODN) in 95D human lung cancer cells could enhance their growth and invasive potential in vitro and in vivo. Here we found that CpG ODN stimulation to 95D cells induced the secretion of HMGB1 in a dose dependent manner. We further showed that blockade of extracellular HMGB1 using A box peptide and ethyl pyruvate significantly abrogated the CpG ODN enhanced progression of 95D cells. Interestingly, we found that HMGB1 alone or acted synergistic with CpG ODN could enhance the progression of 95D cells. Notably, we revealed that RAGE and TLR4 were critical for HMGB1 to exert the synergistic function. We observed a MyD88-dependent upregulation of matrix metalloproteinase (MMP) 2, MMP9 and cyclin-dependent kinase (CDK) 2 in 95D cells in response to HMGB1. These findings might further our understanding of TLR9 signaling in tumor biology and be helpful for developing HMGB1-based strategy against lung cancer.

Antitumor effects of FP3 in combination with capecitabine on PDTT xenograft models of primary colon carcinoma and related lymphatic and hepatic metastases

Ketao Jin, Huanrong Lan, Bojian Xie, Kuifeng He, Zhenzhen Xu, Guangliang Li, Na Han, Lisong Teng and Feilin Cao
Pages 737 - 744
http://dx.doi.org/10.4161/cbt.20556
Abstract | Full Text | PDF

FP3 is an engineered protein which contains the extracellular domain 2 of VEGF receptor 1 (Flt-1) and extracellular domain 3 and 4 of VEGF receptor 2 (Flk-1, KDR) fused to the Fc portion of human immunoglobulin G₁. Previous studies demonstrated its antiangiogenic effects in vitro and in vivo, and its antitumor activity in vivo. In this study, patient-derived tumor tissue (PDTT) xenograft models of primary colon carcinoma and lymphatic and hepatic metastases were established for assessment of the antitumor activity of FP3 in combination with capecitabine. Xenografts were treated with FP3, capecitabine, alone or in combination. After tumor growth was confirmed, volume and microvessel density in tumors were evaluated. Levels of VEGF, and PCNA in the tumor were examined by immunohistonchamical staining, level of thymidine phosphorylase (TP) was examined by ELISA, and levels of related cell signaling pathways proteins expression were examined by western blotting. FP3 in combination with capecitabine showed significant antitumor activity in three xenograft models (primary colon carcinoma, lymphatic metastasis, and hepatic metastasis). The microvessel density in tumor tissues treated with FP3 in combination with capecitabine was lower than that of the control. Antitumor activity of FP3 in combination with capecitabine was significantly higher than that of each agent alone in three xenograft models (primary colon carcinoma, lymphatic metastasis, and hepatic metastasis). This study indicated that addition of FP3 to capecitabine significantly improved tumor growth inhibition in the PDTT xenograft models of primary colon carcinoma and lymphatic and hepatic metastases.

A positive-margin resection model recreates the postsurgical tumor microenvironment and is a reliable model for adjuvant therapy evaluation

Jarrod D. Predina, Brendan Judy, Zvi G. Fridlender, Louis A. Aliperti, Brian Madajewski, Veena Kapoor, Guanjun Cheng, Jon Quatromoni, Olugbenga Okusanya and Sunil Singhal
Pages 745 - 755
http://dx.doi.org/10.4161/cbt.20557
Abstract | Full Text | PDF

Up to 30% of cancer patients undergoing curative surgery develop local recurrences due to positive margins. Patients typically receive adjuvant chemotherapy, immunotherapy and/or radiation to prevent such relapses. Interestingly, evidence supporting these therapies is traditionally derived in animal models of primary tumors, thus failing to consider surgically induced tumor microenvironment changes that may influence adjuvant therapy efficacy. To address this consideration, we characterized a murine model of local cancer recurrence. This model was reproducible and generated a postoperative inflammatory tumor microenvironment that resembles those observed following human cancer surgery. To further validate this model, antagonists of two pro-inflammatory mediators, TGFβ and COX-2, were tested and found to be effective in decreasing the growth of recurrent tumors. We appreciated that preoperative TGFβ inhibition led to wound dehiscence, while postoperative initiation of COX-2 inhibition resulted in a loss of efficacy. In summary, although not an exact replica of all human cancer surgeries, our proposed local recurrence approach provides a biologically relevant and reliable model useful for preclinical evaluation of novel adjuvant therapies. The use of this model yields results that may be overlooked using traditional preclinical cancer models that fail to incorporate a surgical component.

Selenium-containing histone deacetylase inhibitors for melanoma management

Raghavendra Gowda, SubbaRao V. Madhunapantula, Dhimant Desai, Shantu Amin and Gavin P. Robertson
Pages 756 - 765
http://dx.doi.org/10.4161/cbt.20558
Abstract | Full Text | PDF

Melanoma incidence and mortality rates continue to increase each year. Lack of clinically viable agents, drug combinations, effective targeted delivery approaches and success inhibiting targets in tumor tissue have made this disease one of the most difficult to treat, which makes prevention an important option for decreasing disease incidence and mortality rates. Inhibiting histone deacetylases (HDAC) is an approach currently being explored to more effectively treat melanoma but use for prevention has not been explored. In this study, novel selenium containing derivatives of the FDA approved HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) called 5-phenylcarbamoylpentyl selenocyanide (PCP-SeCN) and Bis{5-phenylcarbamoylpentyl} diselenide (B(PCP)-2Se) were created and efficacy tested for preventing early melanocytic lesion development in skin. Topical application of PCP-SeCN and B(PCP)-2Se inhibited melanocytic lesion development in laboratory-generated skin by up to 87% with negligible toxicological effect. Mechanistically, PCP-SeCN and B(PCP)-2Se inhibited HDAC activity and had new inhibitory properties by moderating Akt activity to induce cellular apoptosis as demonstrated by an increase in the sub-G₀-G₁ cell population, and cleaved caspase-3 as well as PARP levels. Furthermore, PCP-SeCN and B(PCP)-2Se inhibited cell proliferation by inhibiting cyclin D1 expression and increasing p21 levels. Thus, PCP-SeCN and B(PCP)-2Se are potential melanoma chemopreventive agents with enhanced efficacy compared with SAHA due to new PI3 kinase pathway inhibitory properties.

HO-3867, a STAT3 inhibitor induces apoptosis by inactivation of STAT3 activity in BRCA1-mutated ovarian cancer cells

Brent J. Tierney, Georgia A. McCann, David E. Cohn, Eric Eisenhauer, Meryl Sudhakar, Periannan Kuppusamy, Kálmán Hideg and Karuppaiyah Selvendiran
Pages 766 - 775
http://dx.doi.org/10.4161/cbt.20559
Abstract | Full Text | PDF

BRCA1 plays an important role in DNA damage and repair, homologous recombination, cell-cycle regulation and apoptosis. BRCA-mutated ovarian cancer often presents at an advanced stage, however, tend to have better response to platinum-based chemotherapy as compared with sporadic cases of epithelial ovarian cancer (EOC). In spite of this, most patients will develop a recurrence and eventually succumb to the disease. Preclinical studies are currently investigating natural compounds and their analogs for tumor-directed targets in ovarian cancer. The aim of this study is to investigate whether the STAT3 inhibitor HO-3867, a novel curcumin analog, has a therapeutic effect on BRCA1-mutated ovarian cancer. Our novel agent, HO-3867 and a commercial STAT3 inhibitor, STATTIC, significantly inhibited BRCA-mutated ovarian cancer cells in vitro in a dose- and time-dependent manner. BRCA-mutated ovarian cancer cells treated with HO-3867 exhibited a significant degree of apoptosis with elevated levels of cleaved caspase-3, caspase-7 and PARP. HO-3867 treatment induced more reactive oxygen species (ROS) in BRCA-mutated cells compared with wild-type cells, however, there was no increased ROS when benign ovarian surface epithelial cells were treated with HO-3867. BRCA1-mutated cancer cells had higher expression of Tyrosine-phosphorylated STAT3 (pTyr705) as compared with other STAT proteins. Furthermore, treatment of these cells with HO-3867 resulted in decreased expression of pTyr705 and its downstream targets cyclin D1, Bcl-2 and survivin. In addition, overexpression of STAT3 cDNA provided resistance to HO-3867-induced apoptosis. Our results show that HO-3867, a potent STAT3 inhibitor, may have a role as a biologically targeted agent for BRCA1-mutated cancers either as an adjunct to cytotoxic chemotherapy or as a single agent.

A comparative study of cell cycle mediator protein expression patterns in anaplastic and papillary thyroid carcinoma

Juanita J. Evans, Henry S. Crist, Saima Durvesh, Richard D. Bruggeman and David Goldenberg
Pages 776 - 781
http://dx.doi.org/10.4161/cbt.20560
Abstract | Full Text | PDF

Anaplastic thyroid carcinoma (ATC) is an extremely aggressive and rapidly fatal neoplasm. The aim of this study was to identify a limited cell cycle associated protein expression pattern unique to ATC and to correlate that pattern with clinical outcome. This represents one of the largest tissue micro-array projects comparing the cell cycle protein expression data of ATC to other well-differentiated tumors in the literature. Tissue microarrays were created from 21 patients with ATC and an age and gender matched cohort of patients with papillary thyroid carcinoma (PTC). Expression of epidermal growth factor receptor, cyclin D1, cyclin E, p53, p21, p16, aurora kinase A, opioid growth factor (OGF), OGF-receptor, thyroglobulin and K_i-67 was evaluated in a semi-quantitative fashion. Differences in protein expression between the cohorts were evaluated using chi-square tests with Bonferroni adjustments. Survival time and presence of metastasis at presentation were collected. The ATC cohort showed a statistically significant decrease (p < 0.05) in thyroglobulin expression and statistically significant increases (p < 0.05) in K_i-67 and p53 expression as compared with the PTC cohort. A trend toward loss of p16 and p21 expression was noted in the ATC cohort. A trend toward decreased survival was noted with p21 expression. These data indicate disruption of the normal cell cycle with aberrant expression of multiple protein markers suggesting increased proliferative activity and loss of control of cell cycle progression to G₁ phase. These findings support the assertion that ATC may represent the furthest end of a continuum of thyroid carcinoma dedifferentiation.

Mesenchymal stem cells in mammary adipose tissue stimulate progression of breast cancer resembling the basal-type

Min Zhao, Patrick C. Sachs, Xu Wang, Catherine I. Dumur, Michael O. Idowu, Valentina Robila, Michael P. Francis, Joy Ware, Matthew Beckman, Aylin Rizki, Shawn E. Holt and Lynne W. Elmore
Pages 782 - 792
http://dx.doi.org/10.4161/cbt.20561
Abstract | Full Text | PDF

Data are accumulating to support a role for adipose-derived mesenchymal stem cells (MSCs) in breast cancer progression; however, to date most studies have relied on adipose MSCs from non-breast sources. There is a particular need to investigate the role of adipose MSCs in the pathogenesis of basal-like breast cancer, which develops at a disproportionate rate in pre-menopausal African-American women with a gain in adiposity. The aim of this study was to better understand how breast adipose MSCs (bMSCs) contribute to the progression of basal-like breast cancers by relying on isogenic HMT-3255 S3 (pre-invasive) and T4-2 (invasive) human cells that upon transplantation into nude mice resemble this tumor subtype. In vitro results suggested that bMSCs may contribute to breast cancer progression in multiple ways. bMSCs readily penetrate extracellular matrix components in part through their expression of matrix metalloproteinases 1 and 3, promote the invasion of T4-2 cells and efficiently chemoattract endothelial cells via a bFGF-independent, VEGF-A-dependent manner. As mixed xenografts, bMSCs stimulated the growth, invasion and desmoplasia of T4-2 tumors, yet these resident stem cells showed no observable effect on the progression of pre-invasive S3 cells. While bMSCs form vessel-like structures within Matrigel both in vitro and in vivo and chemoattract endothelial cells, there appeared to be no difference between T4-2/bMSC mixed xenografts and T4-2 xenografts with regard to intra- or peri-tumoral vascularity. Collectively, our data suggest that bMSCs may contribute to the progression of basal-like breast cancers by stimulating growth and invasion but not vasculogenesis or angiogenesis.

Sorafenib and pemetrexed toxicity in cancer cells is mediated via SRC-ERK signaling

M. Danielle Bareford, Hossein A. Hamed, Jeremy Allegood, Nichola Cruickshanks, Andrew Poklepovic, Margaret A. Park, Besim Ogretmen, Sarah Spiegel, Steven Grant and Paul Dent
Pages 793 - 803
http://dx.doi.org/10.4161/cbt.20562
Abstract | Full Text | PDF

The present studies sought to further understand how the anti-folate pemetrexed and the multi-kinase inhibitor sorafenib interact to kill tumor cells. Sorafenib activated SRC, and via SRC the drug combination activated ERK1/2. Expression of dominant negative SRC or dominant negative MEK1 abolished drug-induced ERK1/2 activation, together with drug-induced autophagy, acidic lysosome formation, and tumor cell killing. Protein phosphatase 2A is an important regulator of the ERK1/2 pathway. Fulvestrant resistant MCF7 cells expressed higher levels of the PP2A inhibitor SET/I2PP2A, had lower endogenous PP2A activity, and had elevated basal ERK1/2 activity compared with their estrogen dependent counterparts. Overexpression of I2PP2A blocked drug-induced activation of ERK1/2 and tumor cell killing. PP2A can be directly activated by ceramide and SET/I2PP2A can be inhibited by ceramide. Inhibition of the de novo ceramide synthase pathway blocked drug-induced ceramide generation, PP2A activation and tumor cell killing. Collectively these findings demonstrate that ERK1/2 plays an essential role downstream of SRC in pemetrexed and sorafenib lethality and that PP2A plays an important role in regulating this process.

AT-406, an orally active antagonist of multiple inhibitor of apoptosis proteins, inhibits progression of human ovarian cancer

Melissa K. Brunckhorst, Dimitry lerner, Shaomeng Wang and Qin Yu
Pages 804 - 811
http://dx.doi.org/10.4161/cbt.20563
Abstract | Full Text | PDF

Ovarian carcinoma is the most deadly gynecological malignancy. Current chemotherapeutic drugs are only transiently effective and patients with advance disease often develop resistance despite significant initial responses. Mounting evidence suggests that anti-apoptotic proteins, including those of the inhibitor of apoptosis protein (IAP) family, play important roles in the chemoresistance. There has been a recent emergence of compounds that block the IAP functions. Here, we evaluated AT-406, a novel and orally active antagonist of multiple IAP proteins, in ovarian cancer cells as a single agent and in the combination with carboplatin for therapeutic efficacy and mechanism of action. We demonstrate that AT-406 has significant single agent activity in 60% of human ovarian cancer cell lines examined in vitro and inhibits ovarian cancer progression in vivo and that 3 out of 5 carboplatin-resistant cell lines are sensitive to AT-406, highlighting the therapeutic potential of AT-406 for patients with inherent or acquired platinum resistance. Additionally, our in vivo studies show that AT-406 enhances the carboplatin-induced ovarian cancer cell death and increases survival of the experimental mice, suggesting that AT-406 sensitizes the response of these cells to carboplatin. Mechanistically, we demonstrate that AT-406 induced apoptosis is correlated with its ability to down-regulate XIAP whereas AT-406 induces cIAP1 degradation in both AT-406 sensitive and resistance cell lines. Together, these results demonstrate, for the first time, the anti-ovarian cancer efficacy of AT-406 as a single agent and in the combination with carboplatin, suggesting that AT-406 has potential as a novel therapy for ovarian cancer patients, especially for patients exhibiting resistance to the platinum-based therapies.

The anti-Fn14 antibody BIIB036 inhibits tumor growth in xenografts and patient derived primary tumor models and enhances efficacy of chemotherapeutic agents in multiple xenograft models

Jennifer S. Michaelson, Rebecca Kelly, Lu Yang, Xiamei Zhang, Kathleen Wortham and Ingrid B.J.K. Joseph
Pages 812 - 821
http://dx.doi.org/10.4161/cbt.20564
Abstract | Full Text | PDF

Agonistic antibodies targeting Fn14, the receptor for TWEAK, have demonstrated anti-tumor activity in xenograft models. Herein, we further explore the therapeutic potential of the humanized anti-Fn14 agonistic antibody, BIIB036, as a single agent and in combination with standard of care cancer therapeutics. Pharmacokinetic studies of BIIB036 in tumor-bearing mice revealed a half-life of approximately three days suggesting twice a week dosing would be necessary to maintain efficacy. However, in multiple xenograft models, BIIB036 treatment resulted in extended tumor growth inhibition up to 40–50 d following cessation of dosing, suggesting that frequent administration of BIIB036 may not be necessary to maintain prolonged anti-tumor activity. Subsequent xenograft studies revealed that maximal efficacy was achieved with BIIB036 dosing once every two weeks, by either intraperitoneal or subcutaneous administration. Xenograft tumors that were initially treated with BIBI036 and then re-grew up to 1000 mm³ following cessation of the first cycle of treatment remained sensitive to a second cycle of treatment. BIIB036 was also evaluated in patient derived primary colon tumor models, where efficacy compared favorably with a standard of care agent. Lastly, BIIB036 enhanced the efficacy of several standard of care chemotherapeutics, including paclitaxel in MDA-MBA-231 breast tumor xenografts, paclitaxel or carboplatin in HOP62 non-small cell lung xenografts, and 5-FU in NCI-N87 gastric xenografts, with no overlapping toxicities. These studies thus establish BIIB036 as a promising therapeutic agent with durable anti-tumor activity in human xenografts as well as patient derived primary tumor models, and enhanced activity and tolerability in combination with standard of care chemotherapeutics. Taken together, the data presented herein suggest that BIIB036 warrants evaluation in the clinic.

PDCD5 promotes cisplatin-induced apoptosis of glioma cells via activating mitochondrial apoptotic pathway

Haiyan Li, Xia Zhang, Xingguo Song, Faliang Zhu, Qun Wang, Chun Guo, Chunmei Liu, Yongyu Shi, Chunhong Ma, Xiaoyan Wang and Lining Zhang
Pages 822 - 830
http://dx.doi.org/10.4161/cbt.20565
Abstract | Full Text | PDF

Glioma is one of the most common primary brain tumors. Despite surgical resection, radiotherapy, and chemotherapy, the prognosis of patients with malignant glioma remains poor. Programmed cell death 5 (PDCD5) is a newly described pro-apoptotic protein. Our previous study showed that PDCD5 downregulation in gliomas was associated with higher pathological grade. Here, we investigated the effect of PDCD5 on chemosensitivity of glioma cells and its mechanism. We demonstrated that overexpression or knockdown of PDCD5 had no significant effect on the proliferation of glioma cell lines (U87, U251, and T98G) in the absence of chemotherapeutic agents. However, PDCD5 overexpression effectively sensitized U87 cells to chemotherapeutic drugs (cisplatin, carboplatin, and vincristine) in a concentration-dependent manner, while its knockdown resulted in decreased chemosensitivity in U251, T98G, and U87 cells. Importantly, expression of PDCD5 also markedly inhibited tumor cell proliferation and colony formation in the presence of low doses of cisplatin. Furthermore, we found that PDCD5 expression promoted cisplatin-induced apoptosis, increased markedly the activation of caspase-3 and caspase-9, and decreased significantly the ratio of Bcl-2/Bax proteins, but had no effect on the activation of caspase-8. Taken together, our findings indicate that PDCD5 promotes chemosensitivity by activating mitochondria-related apoptotic pathway, and that the combination of PDCD5 and chemotherapeutic drugs such as cisplatin, is expected to be an effective therapeutic strategy for the malignant glioma.