UNIPROT:P04637 - FACTA Search

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Query: UNIPROT:P04637 (p53)
77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is no curative treatment for mycosis fungoides (MF), the most common primary cutaneous T-cell lymphoma. The aim of this study was to investigate the response of single lesions to photodynamic therapy (PDT). The study included 10 plaque MF lesions and 2 tumour MF lesions from 10 patients. First, 20% 5-aminolevulinic acid was applied topically to the lesion and adjacent skin for 5-6 h. The lesion was then exposed to red light at around 630nm. Skin biopsies were taken before treatment, after clinical improvement and after clinical remission. The expression of CD3, CD4, CD7, CD8, CD1a, CD34, CD68, CD71, Ki-67, bcl-2 and p53 was studied immunohistochemically. There was complete clinical clearance in seven of nine plaque lesions. Neither tumour lesion responded to PDT. The biopsies confirmed a regression of the infiltrate after treatment. In the sparse remaining infiltrate a few CD4+ and CD8+ cells were found, most of which showed normal bcl-2. There were also fewer proliferating cells, illustrated by a decrease in Ki-67 and CD71. In conclusion, PDT has good clinical and histological effects in treating local plaque MF lesions.
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PMID:Photodynamic therapy with topical 5-aminolevulinic acid for mycosis fungoides: clinical and histological response. 1155 74

Internalization and subcellular fate of free doxorubicin or its polymeric conjugates based on poly N-(2-hydroxypropyl)methacrylamide (pHPMA), either non-targeted or targeted with anti-Thy1.2 or anti-CD71 monoclonal antibody was tested on EL-4 mouse T-cell lymphoma, SW620 human colorectal carcinoma and OVCAR-3 human ovarian adenocarcinoma. Doxorubicin fluorescence allowed us to follow the internalization and intracellular distribution of tested conjugates by laser scanning confocal microscopy and/or by fluorescent microscopy. Whereas free doxorubicin was always detectable only in the nuclei of treated cells, detectable fluorescence of doxorubicin bound to a polymeric carrier, targeted or non-targeted, was detectable up to 3 days of incubation only in the cytoplasmatic structures. While free doxorubicin causes apoptosis in the populations of tested cancer cell lines, significant number of apoptotic cells was never found in cell cultures exposed to targeted or non-targeted polymeric conjugates. In contrast to free doxorubicin, which is a strong inducer of p53 expression, increased p53 expression was never observed after the treatment with the polymeric drug. High-performance liquid chromatographic analysis shows that the percentage of cleaved doxorubicin is very low even after 48 h of incubation of tested cells with the polymeric conjugate, and cannot be the only reason for the toxicity of the conjugate. We suggest that: (a) after the treatment with pHPMA-bound drug, the cells die by necrosis and (b) the toxicity of pHPMA-based conjugates is a combination of the toxic effect of released doxorubicin and the toxic effect of doxorubicin in polymer-bound form directed against cell membranes.
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PMID:Differences in the intracellular fate of free and polymer-bound doxorubicin. 1194 91

Oral squamous cell carcinoma is the most common oral malignancy, and we performed electron microscopic and immunohistochemical investigation of the tumor. In patients with cervical metastasis, microvilli were developed and a small number of desmosomes were found, regardless of the width of the intercellular spaces. In patients without the metastasis, few microvilli were found in relatively wide intercellular spaces, or numerous microvilli were found in narrow intercellular spaces, and a large number of desmosomes were shown. However, these findings were different from those of tumors that had received radiotherapy, in which numerous microvilli and a small number of desmosomes were found in the nonmetastatic cases. Transferrin receptor, which is a marker of cell proliferation, was localized on the cell membrane, especially in microvilli. Ultrastructural similarity between the primary tumor and the metastatic tumor was recognized, however, the features of microvilli, desmosomes, and the intercellular spaces differed between them in most cases. It is suggested that microvilli might be related to the metastasis of oral squamous cell carcinoma cells. Immunohistochemically, the protein expression of p53 and pRb2/p130 was related to the clinical course of the patients with oral squamous cell carcinoma; the mechanism of the synthesis of these proteins should be investigated in order to understand the biological behavior of the tumor.
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PMID:Oral squamous cell carcinoma: electron microscopic and immunohistochemical characteristics. 1235 33

An ideal therapeutic for cancer would be one that selectively targets to tumor cells, is nontoxic to normal cells, and that could be systemically delivered, thereby reaching metastases as well as primary tumor. Immunoliposomes directed by monoclonal antibody or its fragments are promising vehicles for tumor-targeted drug delivery. However, there is currently very limited data on gene delivery using these vehicles. We have recently described a cationic immunoliposome system directed by a lipid-tagged, single-chain antibody Fv fragment (scFv) against the human transferrin receptor (TfR) that shows promising efficacy for systemic p53 tumor suppressor gene therapy in a human breast cancer metastasis model. However, the extremely low yield of this lipid-tagged scFv limited further downstream development and studies. Here we report a different expression strategy for the anti-TfR scFv, which produces high levels of protein without any tags, and a different approach for complexing the targeting scFv to the liposomes. This approach entails covalently conjugating the scFv to the liposome via a cysteine at the 3'-end of the protein and a maleimide group on the liposome. Our results show that this conjugation does not impair the immunological activity or targeting ability of the scFv. The scFv-cys targets the cationic liposome-DNA complex (lipoplex) to tumor cells and enhances the transfection efficiencies both in vitro and in vivo in a variety of human tumor models. This scFv-immunoliposome can deliver the complexed gene systemically to tumors in vivo, where it is efficiently expressed. In comparison with the whole antibody or transferrin molecule itself, the scFv has a much smaller size for better penetration into solid tumors. It is also a recombinant protein rather than a blood product; thus, large scale production and strict quality control are feasible. This new approach provides a promising system for tumor-targeted gene delivery that may have potential for systemic gene therapy of various human cancers.
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PMID:Systemic tumor-targeted gene delivery by anti-transferrin receptor scFv-immunoliposomes. 1248 50

Iron (Fe) chelators are potential antitumor agents. Cellular Fe depletion results in a G1/S arrest but the precise molecular mechanisms involved remain unclear. Recent studies have shown that this process is complex with multiple cell cycle molecules being involved. We previously showed that Fe chelators such as 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) were far more potent antitumor agents than the clinically used ligand, desferrioxamine (DFO). To further characterize the effects of chelators on cell cycle arrest, we compared their activity with the DNA-damaging agents actinomycin D (Act D) and cisplatin (CP). These latter two compounds increase the expression of p53 and its target genes such as the universal cyclin-dependent kinase inhibitor, p21(CIP1/WAF1). Incubation of normal and neoplastic cells with all agents resulted in increased nuclear p53, the effect being pronounced for Act D and CP. As expected, both Act D and CP also markedly increased nuclear p21(CIP1/WAF1) protein levels, while DFO and 311 caused a significant (P<0.0004) decrease. This latter effect was surprising, as these chelators markedly increased mRNA levels of this molecule. Immunofluorescence studies showed that Act D and CP caused nuclear localization of p21(CIP1/WAF1). In contrast, the chelators prevented translation of p21(CIP1/WAF1). This did not appear to be due to a general effect of the chelators on preventing translation, as transferrin receptor 1 was markedly up-regulated 15- to 21-fold by DFO and 311. Combination of 311 with Act D or CP prevented translation of p21(CIP1/WAF1) and its nuclear localization observed with these DNA-damaging agents. Significantly, the effect of chelation on reducing nuclear p21(CIP1/WAF1) was reversed by the Fe donor ferric ammonium citrate, indicating that p21(CIP1/WAF1) translation was dependent on intracellular Fe levels. This study demonstrates that while Fe chelators markedly up-regulate the mRNA levels of p21(CIP1/WAF1) they paradoxically inhibit translation.
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PMID:Potent iron chelators increase the mRNA levels of the universal cyclin-dependent kinase inhibitor p21(CIP1/WAF1), but paradoxically inhibit its translation: a potential mechanism of cell cycle dysregulation. 1280 43

KP1019 [indazolium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] (FFC14A) is a metal complex with promising anticancer activity. Since chemoresistance is a major obstacle in chemotherapy, this study investigated the influence of several drug resistance mechanisms on the anticancer activity of KP1019. Here we demonstrate that the cytotoxic effects of KP1019 are neither substantially hampered by overexpression of the drug resistance proteins multidrug resistance-related protein 1, breast cancer resistance protein, and lung resistance protein nor the transferrin receptor and only marginally by the cellular p53 status. In contrast, P-glycoprotein overexpression weakly but significantly (up to 2-fold) reduced KP1019 activity. P-glycoprotein-related resistance was based on reduced intracellular KP1019 accumulation and reversible by known P-glycoprotein modulators. KP1019 dose dependently inhibited ATPase activity of P-glycoprotein with a K(i) of approximately 31 microM. Furthermore, it potently blocked P-glycoprotein-mediated rhodamine 123 efflux under serum-free conditions (EC(50), approximately 8 microM), however, with reduced activity at increased serum concentrations (EC(50) at 10% serum, approximately 35 microM). Moreover, P-glycoprotein-mediated daunomycin resistance could only be marginally restored by KP1019 in serum-containing medium, also indicating an influence of serum proteins on the interaction between KP1019 and P-glycoprotein. Acquired KP1019 resistance was investigated by selecting KB-3-1 cells against KP1019 for more than 1 year. Only an approximately 2-fold KP1019 resistance could be induced, which unexpectedly was not due to overexpression of P-glycoprotein or other efflux pumps. Accordingly, KP1019-resistant cells did not display reduced drug accumulation. Their unique cross-resistance pattern confirmed an ABC transporter-independent resistance phenotype. In summary, the likeliness of acquiring insensitivity to KP1019 during therapy is expected to be low, and resistance should not be based on overexpression of drug efflux transporters.
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PMID:Intrinsic and acquired forms of resistance against the anticancer ruthenium compound KP1019 [indazolium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] (FFC14A). 1533 56

Iron(II) heme-mediated activation of the peroxide bond of artemisinins is thought to generate the radical oxygen species responsible for their antimalarial activity. We analyzed the role of ferrous iron in the cytotoxicity of artemisinins toward tumor cells. Iron(II)-glycine sulfate (Ferrosanol) and transferrin increased the cytotoxicity of free artesunate, artesunate microencapsulated in maltosyl-beta-cyclodextrin, and artemisinin toward CCRF-CEM leukemia and U373 astrocytoma cells 1.5- to 10.3-fold compared with that of artemisinins applied without iron. Growth inhibition by artesunate and ferrous iron correlated with induction of apoptosis. Cell cycle perturbations by artesunate and ferrous iron were not observed. Treatment of p53 wild-type TK6 and p53 mutated WTK1 lymphoblastic cells showed that mutational status of the tumor suppressor p53 did not influence sensitivity to artesunate. The effect of ferrous iron and transferrin was reversed by monoclonal antibody RVS10 against the transferrin receptor (TfR), which competes with transferrin for binding to TfR. CCRF-CEM and U373 cells expressed TfR in 95 and 48% of the cell population, respectively, whereas TfR expression in peripheral mononuclear blood cells of four healthy donors was confined to 0.4-1.3%. This indicates that artemisinins plus ferrous iron may affect tumor cells more than normal cells. The IC(50) values for a series of eight different artemisinin derivatives in 60 cell lines of the U.S. National Cancer Institute were correlated with the microarray mRNA expression of 12 genes involved in iron uptake and metabolism by Kendall's tau test to identify iron-responsive cellular factors enhancing the activity of artemisinins. This pointed to mitochondrial aconitase and ceruloplasmin (ferroxidase).
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PMID:Enhancement of cytotoxicity of artemisinins toward cancer cells by ferrous iron. 1533 16

Nearly all cervical cancers are etiologically attributable to human papillomavirus (HPV) infection and pharmaceutical treatments targeting HPV-infected cells would be of great medical benefit. Because many neoplastic cells (including cervical cancer cells) overexpress the transferrin receptor to increase their iron uptake, we hypothesized that iron-dependent, antimalarial drugs such as artemisinin might prove useful in treating HPV-infected or transformed cells. We tested three different artemisinin compounds and found that dihydroartemisinin (DHA) and artesunate displayed strong cytotoxic effects on HPV-immortalized and transformed cervical cells in vitro with little effect on normal cervical epithelial cells. DHA-induced cell death involved activation of the mitochondrial caspase pathway with resultant apoptosis. Apoptosis was p53 independent and was not the consequence of drug-induced reductions in viral oncogene expression. Due to its selective cytotoxicity, hydrophobicity, and known ability to penetrate epithelial surfaces, we postulated that DHA might be useful for the topical treatment of mucosal papillomavirus lesions. To test this hypothesis, we applied DHA to the oral mucosa of dogs that had been challenged with the canine oral papillomavirus. Although applied only intermittently, DHA strongly inhibited viral-induced tumor formation. Interestingly, the DHA-treated, tumor-negative dogs developed antibodies against the viral L1 capsid protein, suggesting that DHA had inhibited tumor growth but not early rounds of papillomavirus replication. These findings indicate that DHA and other artemisinin derivatives may be useful for the topical treatment of epithelial papillomavirus lesions, including those that have progressed to the neoplastic state.
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PMID:Dihydroartemisinin is cytotoxic to papillomavirus-expressing epithelial cells in vitro and in vivo. 1632 32

One of the most intriguing biological subjects is cell-surface molecules that regulate the susceptibility of human cells to cell-killing effects after irradiation with far-ultraviolet light (UV, principally 254 nm wavelength). Human RSa cells have unusual sensitivity to UV-induced cell-killing. We searched for molecules on the cell-surface of RSa cells that were present in different amounts as compared to a variant of these cells, UV(r)-1 cells, which have increased resistance to UV cell-killing. Among the 21 molecules examined, the amount of transferrin receptor (TfR) protein was found to be 2-fold higher in UV(r)-1 cells compared with in RSa cells. The amounts of this protein were also higher in the UV-resistant hematopoietic cell lines, CEM6 and Daudi, as compared to the UV-sensitive cell lines, Molt4 and 697. Culturing of UV(r)-1 cells in a medium containing anti-transferrin antibodies resulted in sensitization of the cells to UV cell-killing as demonstrated by colony formation assay. Similar results were observed by treatment of the cells with TfR siRNA. In contrast, overexpression of TfR protein led to a resistance to UV cell-killing in RSa cells and monkey COS7 cells as demonstrated by both colony formation and apoptosis assay. In TfR-overexpressing cells, reduction of p53 and Bax protein was observed after UV-irradiation. Thus, TfR expression appears to be involved in the regulation of UV-resistance, possibly via modulation of the amount of p53 and Bax protein.
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PMID:Enhanced expression of transferrin receptor confers UV-resistance in human and monkey cells. 1639 35

Iron-containing antianemic drug ferric-sorbitol-citrate (FSC) inhibits the proliferation of various cancer cell lines in vitro and causes a regression of experimental murine tumors in vivo but does not affect the proliferation of nonmalignant cells. Growth modification caused by FSC iron involves a diminished expression of Bcl-2 and an overexpression of p53 proto-oncogene, accompanied by an increased incidence of apoptosis. Aiming to evaluate further the activity principle of the anticancer effects of this antianemic drug, in this study, we analyzed the utilization of iron from FSC and the effects of FSC iron on transferrin receptor 1 (TfR1) and ferritin expression. Without FSC iron, all the cell lines had an equal expression of TfR1, but if cultured in FSC-supplemented medium, human colon SW620 and laryngeal carcinoma Hep cells exhibited a lower expression of TfR1-positive cells than nonmalignant Wi38 fibroblasts and pancreatic carcinoma MiaPaCa2 cells. The most sensitive to FSC iron were colon carcinoma SW620 cells, whereas Wi38 fibroblasts were not sensitive at all. Increased iron uptake by colon carcinoma cells was noticed in the first 3 hours of the incubation with FSC iron, whereas higher FSC iron concentrations and longer incubation also impaired ferritin expression in SW260 colon carcinoma cells. Thus, the anticancer ability of FSC could result from its higher initial utilization of iron and consecutive negative signal for the expression of TfR1 in tumor cells. Tumor cells containing lower amounts of ferritin are probably more sensitive to oxidative stress caused by iron overload, whereas FSC iron itself was proven to be chemically stable and did not induce lipid peroxidation.
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PMID:Uptake of anti-anemic substance ferric-sorbitol-citrate by normal and malignant cells and its effects on expression of transferrin receptor 1 and ferritin. 1725 79

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