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Biomedical subjects

G Cuccuru

Publications and source records attributed to G Cuccuru.

7 recordsLinked to original sources
PubMed2003

Inactivation of Ret/Ptc1 oncoprotein and inhibition of papillary thyroid carcinoma cell proliferation by indolinone RPI-1.

Genetic alterations causing oncogenic activation of the RET gene are recognized as pathogenic events in papillary and medullary thyroid carcinomas. Inhibition of Ret oncoprotein functions could thereby represent a specific therapeutic approach. We previously described the inhibitory activity of the 2-indolinone derivative RPI-1 (formerly Cpdl) on the tyrosine kinase activity and transforming ability of the products of the RET/PTC1 oncogene exogenously expressed in murine cells. In the present study, we investigated the effects of RPI-1 in the human papillary thyroid carcinoma cell line TPC-1 spontaneously harboring the RET/PTC1 rearrangement. Treatment with RPI-1 inhibited cell proliferation and induced accumulation of cells at the G2 cell cycle phase. In treated cells, Ret/Ptc1 tyrosine phosphorylation was abolished along with its binding to Shc and phospholipase C(gamma), thereby indicating abrogation of constitutive signaling mediated by the oncoprotein. Activation of JNK2 and AKT was abolished, thus supporting the drug inhibitory efficacy on downstream pathways. In addition, cell growth inhibition was associated with a reduction in telomerase activity by nearly 85%. These findings in a cellular context relevant to the pathological function of RET oncogenes support the role of Ret oncoproteins as useful targets for therapeutic intervention, and suggest RPI-1 as a promising candidate for preclinical development in the treatment of thyroid tumors expressing RET oncogenes.

Animals↗
PubMed2001

Cell cycle checkpoint efficiency and cellular response to paclitaxel in prostate cancer cells.

BACKGROUND: Defects in the cell cycle machinery of prostate cancer cells might impair the efficiency of cell cycle checkpoints and affect the cell response to chemotherapeutic drugs. We examined the relationship between the status of microtubule damage-activated checkpoints and the response of hormone-refractory prostate cancer cells to paclitaxel. METHODS: The two cell lines DU145 and PC3 harboring defects at proteins involved in the regulation of checkpoints activated by microtubule damage were examined for cell sensitivity, apoptotic response, and efficiency of checkpoints in response to paclitaxel. RESULTS: In spite of a comparable sensitivity to the antiproliferative effects of paclitaxel, DU145 and PC3 cells exhibited different cell cycle control at checkpoints activated by microtubule damage. A transient mitotic arrest was induced by the taxane in both cell lines. However, PC3 cells underwent a rapid mitotic slippage and displayed a defective postmitotic checkpoint as evidenced by the appearance of polyploid cells. In this cell line, paclitaxel-induced cell death was a slow and delayed event, occurring also after S-phase re-entry. The mitotic checkpoint appeared to be more stringent in DU145 cells compared to PC3 cells. Moreover, despite the expression of mutated proteins involved in the prevention of DNA endoreduplication (p53, pRb, and p16(INK4A)), these cells did not progress into the cell cycle but efficiently underwent apoptosis by 24 hr. Such a response of DU145 cells was associated with phosphorylation of the p21(WAF1) protein. CONCLUSIONS: These observations evidence that activation of checkpoints following microtubule damage in prostate cancer may be regulated through complex mechanisms possibly involving p21(WAF1). Our findings support that the status of cell cycle checkpoints might affect the modality of cell death. However, the relevance of the mode of cell death for the sensitivity to taxanes remains to be determined.

Antineoplastic Agents, Phytogenic↗
PubMed2000

Clavilactones, a novel class of tyrosine kinase inhibitors of fungal origin.

Targeting of deregulated protein tyrosine kinases has been proposed as a new approach in the therapeutic intervention against pathological processes including proliferative disorders and cancer. Using a screening approach based on a comparative evaluation of antiproliferative effects in a panel of tumor cells with differential expression of protein tyrosine kinases, three benzoquinoid macrolidic fungal metabolites produced by Clitocybe clavipes, clavilactones A, B, and D (CA, CB, and CD) and two semisynthetic derivatives of these products, diacetyl-CA and dimethyl-CA, were identified as inhibitors of protein tyrosine kinases. Naturally occurring CA, CB, and CD showed inhibitory activity in kinase assays against the Ret/ptc1 and epidermal growth factor receptor (EGF-R) tyrosine kinases, while being less effective against the v-Abl tyrosine kinase and p34(cdc2) serine/threonine kinase (IC(50) 2.8, 5.5, 81.3, and 128 microM respectively, for the most potent compound CD). CB was shown to be a non-competitive inhibitor of EGF-R with respect to ATP or poly(Glu(6)Ala(3)Tyr). CD also preferentially inhibited the growth of A431 cells, which overexpress a constitutively active EGF-R, as opposed to IGROV-1 and SKOV-3 cells, which express low levels of the receptor. Further, EGF-R was shown to be a target for clavilactones in A431 cells, since EGF-induced receptor autophosphorylation was inhibited in the presence of CB, CD, and diacetyl-CA. Both CD and diacetyl-CA displayed weak activity when administered daily (i.p.) to mice bearing ascitic A431 tumor. These findings indicate that clavilactones represent the prototypes of a new structural class of tyrosine kinase inhibitors deserving further investigation.

Agaricales↗
PubMed1984

[Nutritional habits of homozygote beta-thalassemic subjects].

An investigation on eating habits of a group of 40 patients with beta-thalassemia major has been carried out mainly to evidentiate iron intake whose absorption is strikingly increased in this disease. Questionnaires were used to obtain information. Daily food intake, the mean consumption of various types of food and the level of the more significant nutrients were calculated, using the National Institute of Nutrition tables. A high consumption of meat and a low consumption of fruits and vegetables were observed. A high proportion of proteins (particularly of animal origin) and a low proportion of lipids and carbohydrates was observed in comparison with the recommended levels of nutrients. Iron intake was slightly lower but its absorption may be increased because of the high proportion of calories of animal origin. A manipulation of the diet seems to be necessary to reduce the risk of iron loading.

Adolescent↗