A cell-penetrating peptidic GRP78 ligand for tumor cell-specific prodrug therapy

Yoneda, Yasuko; Steiniger, Sebastian C.J.; Čapková, Kateřina; Mee, Jenny M.; Liu, Ying; Kaufmann, Gunnar F.; Janda, Kim D.

doi:10.1016/j.bmcl.2008.01.060

Cited by 74 publications

(64 citation statements)

References 16 publications

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“…For example, Artemisinin is a natural product isolated from Artemisia annua L. Oh et al reported that the artemisininpeptide conjugates showed potent anticancer activity against Molt-4 leukemia cells with a significantly improved cancer/normal cells selectivity (26). Pep42, a cyclic 13-mer oligopeptide that specifically binds to glucose-regulated protein 78 (GRP78) and internalizes into cancer cells, represents an excellent vehicle for tumor cell-specific chemotherapy (27). In addition, the non-immunogenicity of micro-peptides, especially of dipeptides and tripeptides, shows biological effects and ensures that consumers are free of anaphylaxis (28).…”

Section: Discussionmentioning

confidence: 99%

Anticancer bioactive peptide suppresses human gastric cancer growth through modulation of apoptosis and the cell cycle

2009

Oncol Rep

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Abstract. Anticancer bioactive peptide (ACBP) was extracted from goat spleens with immunization by human gastric cancer extracts. ACBP was biochemically purified and identified as ~8,000 Da peptide. Here we report that ACBP significantly inhibited the growth of human gastric cancer line BGC-823 in vitro in a dose-dependent manner. ACBP induced BGC-823 cell apoptosis was observed morphologically both by light microscopy and electronic microscopy; and ACBPinduced apoptosis and G 0 /G 1 cell cycle arrest were quantified by Annexin V-FITC/PI staining and flow cytometry. At the molecular level, ACBP induced p16 Ink4 , p21 Waf1 , p27 Kip1 , and bax tumor suppressor and apoptotic gene expression, as well as inhibited cyclin D1, c-myc, and bcl-2 gene expression that promote tumorigenesis. In vivo, ACBP dramatically inhibited human gastric tumor growth in a xenograft model with no apparent cytotoxicity to host. Our study suggests that ACBP could be a powerful anticancer biological product through induction of cell apoptosis and cell cycle arrest.

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Section: Discussionmentioning

confidence: 99%

Anticancer bioactive peptide suppresses human gastric cancer growth through modulation of apoptosis and the cell cycle

2009

Oncol Rep

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“…Therapeutics targeting GRP78 have recently emerged and have shown anti-tumor activity in solid tumors. 16,[51][52][53][54] Whether these and other agents capable of suppressing GRP78 expression or activity can be applied for suppression of leukemogenesis warrants vigorous investigation.…”

Section: Discussionmentioning

confidence: 99%

Inducible knockout of GRP78/BiP in the hematopoietic system suppresses Pten-null leukemogenesis and AKT oncogenic signaling

Wey

Luo

Tseng

et al. 2012

Blood

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Traditionally, GRP78 is regarded as protective against hypoxia and nutrient starvation prevalent in the microenvironment of solid tumors; thus, its role in the development of hematologic malignancies remains to be determined. To directly elucidate the requirement of GRP78 in leukemogenesis, we created a biallelic conditional knockout mouse model of GRP78 and PTEN in the hematopoietic system. Strikingly, heterozygous knockdown of GRP78 in PTEN null mice is sufficient to restore the hematopoietic stem cell population back to the normal percentage and suppress leukemic blast cell expansion. AKT/mTOR activation in PTEN null BM cells is potently inhibited by Grp78 heterozygosity, corresponding with suppression of the PI3K/AKT pathway by GRP78 knockdown in leukemia cell lines. This is the first demonstration that GRP78 is a critical effector of leukemia progression, at least in part through regulation of oncogenic PI3K/AKT signaling. In agreement with PI3K/AKT as an effector for cytosine arabinoside resistance in acute myeloid leukemia, overexpression of GRP78 renders human leukemic cells more resistant to cytosine arabinoside-induced apoptosis, whereas knockdown of GRP78 sensitizes them. These, coupled with the emerging association of elevated GRP78 expression in leukemic blasts of adult patients and early relapse in childhood leukemia, suggest that GRP78 is a novel therapeutic target for leukemia. (Blood. 2012;119(3):817-825) IntroductionOne of the most frequently mutated tumor suppressor genes in human cancer is PTEN (phosphatase and tension homolog deleted on chromosome 10), which encodes for a nonredundant, plasmamembrane lipid phosphatase that antagonizes the phosphatidylinositol-3-kinase (PI3K) signaling pathway. 1,2 On loss of PTEN, the PI3K/AKT signaling pathway is activated, leading to promotion of cell survival, proliferation, and angiogenesis, as well as activation of the mTOR and S6 kinases, resulting in enhanced protein translation commonly observed in cancers. 3 PTEN also has a role in the maintenance of the hematopoietic stem cells (HSCs), as shown by ablation of PTEN function in adult HSCs through crossing of polyinosine-polycytidine (pIpC)-inducible Mx-1-Cre transgenic mouse line 4 with a Pten flox/flox (Pten f/f ) mouse line. 5 Induced Cre expression in postnatal mice exhausted normal HSCs and promoted excessive proliferation of leukemogenic stem cells, resulting in the development of myeloproliferative disorders (MPDs) and eventually leukemia. 6,7 These studies further showed that the mTOR inhibitor rapamycin effectively suppressed growth of the leukemogenic stem cells and prevented exhaustion of normal HSCs. Furthermore, recent studies have shown that PTEN is down-regulated by BCR-ABL in leukemic stem cells, and PI3K and AKT play critical roles in BCR-ABL-induced leukemia in mice. 8,9 Thus, inhibition of the PTEN/AKT/mTOR pathway not only can suppress solid tumor growth but could also represent a novel therapeutic strategy against stem cell disorders that are leukemogenic in nature.GRP78, also ref...

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“…Therefore, it presents an effective prodrug-conjugated vehicle for a large number of cytotoxic drugs in order to accurately target neoplasm [Yoneda et al, 2008]. For instance, by means of cellular uptake and intracellular trafficking, its conjugate with taxol promotes apoptosis of tumor cells, especially the highly metastatic ones [Arap et al, 2004].…”

Section: Targeting Grp78 Therapeuticsmentioning

confidence: 99%

Roles of GRP78 in physiology and cancer

Zhang

2010

J of Cellular Biochemistry

161

110

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As one member of 70 kDa heat shock proteins, glucose-regulated protein 78 (GRP78) participates in protein folding, transportation and degradation. This sort of capacity can be enhanced by stresses under which GRP78 is induced rapidly. Unlike its homologues, GRP78 presents multifaceted subcellular position: When ER retention, it serves as the switch of unfolded protein response; When mitochondrial binding, it directly interacts with apoptotic executors; When cell surface residing, it recognizes extracellular ligands, transducing proliferative signals, especially in certain tumors. The close correlation between GRP78 and neoplasm provides us further insight into the event of carcinogenesis and cancer cell chemoresistance, indicating its prognostic predicting significance and validating potential therapeutics for clinical usage, especially because its small molecular inhibitors are emerging quickly these years. What's more, GRP78-related signaling may be helpful for clearer understanding of its biological mechanisms.

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A cell-penetrating peptidic GRP78 ligand for tumor cell-specific prodrug therapy

Cited by 74 publications

References 16 publications

Anticancer bioactive peptide suppresses human gastric cancer growth through modulation of apoptosis and the cell cycle

Anticancer bioactive peptide suppresses human gastric cancer growth through modulation of apoptosis and the cell cycle

Inducible knockout of GRP78/BiP in the hematopoietic system suppresses Pten-null leukemogenesis and AKT oncogenic signaling

Roles of GRP78 in physiology and cancer

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