<i>Survivin</i>and Granzyme B–induced apoptosis, a novel anticancer therapy

Caldas, Hugo; Jaynes, Florinda O.; Boyer, Michael W.; Hammond, Sue; Altura, Rachel A.

doi:10.1158/1535-7163.mct-05-0423

Cited by 28 publications

(18 citation statements)

References 42 publications

(39 reference statements)

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“…For systemic in vivo delivery, transfection agents based on polyethylenimine (PEI) have shown the most promise (18,19). One of the most effective formulations, in vivo-jetPEI (Polyplus Transfection), has been evaluated for gene delivery in a number of cancer models in vivo (20)(21)(22)(23)(24)(25)(26), although rarely via systemic injection (27)(28)(29), as well as in several clinical trials for heart disease (30), HIV (31), and cancer (32). Because s.c. tumor models might not faithfully reflect the architecture of internal tumors, we elected to use a model established by intrasplenic injection of the HCT116 line of human colorectal cancer cells in NOD-SCID-IL-2Rγ-deficient mice (NOG mice) (33).…”

Section: Resultsmentioning

confidence: 99%

A nanoparticle formulation that selectively transfects metastatic tumors in mice

Yang

Hendricks

Liu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Nanoparticle gene therapy holds great promise for the treatment of malignant disease in light of the large number of potent, tumorspecific therapeutic payloads potentially available for delivery. To be effective, gene therapy vehicles must be able to deliver their therapeutic payloads to metastatic lesions after systemic administration. Here we describe nanoparticles comprised of a core of high molecular weight linear polyethylenimine (LPEI) complexed with DNA and surrounded by a shell of polyethyleneglycol-modified (PEGylated) low molecular weight LPEI. Compared with a stateof-the-art commercially available in vivo gene delivery formulation, i.v. delivery of the core/PEGylated shell (CPS) nanoparticles provided more than a 16,000-fold increase in the ratio of tumor to nontumor transfection. The vast majority of examined liver and lung metastases derived from a colorectal cancer cell line showed transgene expression after i.v. CPS injection in an animal model of metastasis. Histological examination of tissues from transfected mice revealed that the CPS nanoparticles selectively transfected neoplastic cells rather than stromal cells within primary and metastatic tumors. However, only a small fraction of neoplastic cells (<1%) expressed the transgene, and the extent of delivery varied with the tumor cell line, tumor site, and host mouse strain used. Our results demonstrate that these CPS nanoparticles offer substantial advantages over previously described formulations for in vivo nanoparticle gene therapeutics. At the same time, they illustrate that major increases in the effectiveness of such approaches are needed for utility in patients with metastatic cancer.

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Section: Resultsmentioning

confidence: 99%

A nanoparticle formulation that selectively transfects metastatic tumors in mice

Yang

Hendricks

Liu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The enhanced expression of survivin mRNA in SCLC cell lines as compared to NSCLC cell lines (55, and the present study) suggests that the transcriptional upregulation of BIRC5 gene expression in NSCLC and SCLC cells may be different. Altogether, the high overexpression of the BIRC5 gene in lung tumours offers the rationale for their apoptosis-based therapy that could involve the tumour-specific expression of recombinant DNA constructs consisting of a fusion of the BIRC5 promoter to the coding sequence of an active apoptosis effector such as reverse caspases or granzyme B (73,74).…”

Section: ------------------------------------------------------------mentioning

confidence: 99%

Increased expression of inhibitor of apoptosis proteins, survivin and XIAP, in non-small cell lung carcinoma

Kr̆epela

Dankova²,

Moravcikova³

et al. 2009

Int J Oncol

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Abstract.Members of the inhibitor of apoptosis protein (IAP) family, survivin and X-chromosome-linked IAP (XIAP), contribute to apoptosis resistance of cancer cells, and an increase in their expression may elevate the apoptotic threshold of malignant tumours during their growth and progression. In the present study, we investigated the expression status of survivin and its interactants hepatitis B X-interacting protein (HBXIP) and XIAP in non-small cell lung carcinoma (NSCLC) cell lines and NSCLC tumours and matched lungs from surgically treated patients in relation to their clinicopathological data. The expression of survivin, HBXIP and XIAP mRNAs was quantitated by real-time RT-PCR. The expression of survivin and XIAP proteins was analysed by Western blotting and ELISA. Survivin mRNA and protein levels were highly upregulated in NSCLC cells and tissues as compared to the lungs. In fact, the levels of survivin mRNA and protein in the tumours were more than 10-fold higher in 96 (64%) and 72 (82%) of the 150 and 88 examined NSCLC patients, respectively. The expression of survivin mRNA was higher in squamous cell lung carcinomas than in lung adenocarcinomas (LACs; P=0.003) and in less-differentiated tumours than in well-differentiated ones (P=0.007). The level of survivin protein was higher in stage IB and stage II+III tumours (P=0.049 and P=0.044), than in stage IA tumours. The BIRC5 promoter polymorphism at nucleotide -31 did not influence the expression of survivin mRNA and protein in NSCLC cells and tumours. HBXIP mRNA was abundantly expressed in NSCLC cell lines and NSCLC tumours and lungs, while its level was comparable in the tumours and lungs. The expression of XIAP mRNA in NSCLC cell lines and NSCLC tumours and lungs was not significantly different. However, the expression of XIAP protein was higher in NSCLC tumours, particularly in LACs, as compared to the lungs (P=0.017 and P=0.004). In conclusion, the overexpression of survivin in the majority of NSCLCs together with the abundant or upregulated expression of HBXIP and XIAP suggest that tumours are endowed with resistance against a variety of apoptosis-inducing conditions.

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“…As the important IAPs members, XIAP (X-linked inhibitor of apoptosis) and survivin are up-regulated in most human tumor cells and make the cancer cells escape from apoptosis. Evidence indicates that survivin and XIAP are associated with chemoresistance and decrease of these IAPs induced apoptosis in chemoresistant human ovarian cancer cells (31,32). In the present study, we have investi-gated the regulation and role of two anti-apoptotic factors, survivin and XIAP, in ovarian cancer cells, and tried to explain their relationship with cellular resistance to paclitaxel.…”

Section: Discussionmentioning

confidence: 91%

Emodin sensitizes paclitaxel-resistant human ovarian cancer cells to paclitaxel-induced apoptosis in vitro

Liu²,

Mao³

et al. 2009

Oncol Rep

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Abstract. Ovarian cancer has the highest mortality rate among gynecologic malignancies in the world, and the development of drug resistance is a major impediment toward successful treatment of the desease. Emodin has been reported to sensitize human tumor cells to chemotherapeutic agents. The present study investigated whether emodin could overcome chemoresistance of A2780/taxol cells. Cells were treated with different concentration of emodin alone or combined with paclitaxel, then the cell viability was measured by MTT and the apoptosis was determined by flow cytometric analysis. The changes of mRNA and protein were examined by QRT-PCR and Western blotting. The function of P-glycoprotein was also determined by flow cytometry. The results showed that emodin induced apoptosis alone at a high concentration and increased paclitaxel-induced apoptosis at a low concentration. It enhanced the sensitivity of A2780/taxol cells to paclitaxel with down-regulation of P-glycoprotein, XIAP and survivin. Taken together, the results demonstrated a dual role for emodin in the inhibition of drug resistant ovarian tumor growth by increasing paclitaxel cellular concentration and re-sensitizing the resistant cells to paclitaxel. Our results suggest the possibility of an innovative chemotherapeutic strategy that uses emodin in combination with paclitaxel to increase the sensitivity of tumor cells.

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Survivinand Granzyme B–induced apoptosis, a novel anticancer therapy

Abstract: Survivin is an antiapoptotic protein highly expressed in malignant cells that confers resistance to cytotoxic therapy. Granzyme B is a potent cytotoxic protein that is released from mammalian natural killer cells and CTLs following noxious stimuli, including foreign invaders.

Cited by 28 publications

References 42 publications

A nanoparticle formulation that selectively transfects metastatic tumors in mice

A nanoparticle formulation that selectively transfects metastatic tumors in mice

Increased expression of inhibitor of apoptosis proteins, survivin and XIAP, in non-small cell lung carcinoma

Emodin sensitizes paclitaxel-resistant human ovarian cancer cells to paclitaxel-induced apoptosis in vitro

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