Involvement of the α Isoenzyme of Protein Kinase C in the Growth Inhibition Induced by Phorbol Esters in MH1C1 Hepatoma Cells

Perletti, Gian Paolo; Smeraldi, Carla; Porro, Danilo; Piccinini, F

doi:10.1006/bbrc.1994.2848

Cited by 27 publications

(11 citation statements)

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“…Our observations with myoblasts are in agreement with recent reports indicating that PKC ␣ mediates proliferative events in different cell systems [Battaini et al, 1994;Wooten et al, 1992;Perletti et al, 1994]. In addition, there is also evidence involving the ␤, ␦, and ⑀ isozymes of PKC in the differentiation of various cell types other than muscle [O'Driscoll et al, 1995;Beckman et al, 1990;Doi et al, 1994].…”

Section: Discussionsupporting

confidence: 94%

Evidence on the participation of protein kinase C ? in the proliferation of cultured myoblasts

et al. 1999

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There is evidence involving protein kinase C (PKC) in the signal transduction pathways that regulate the differentiation of myoblasts into mature multinucleated muscle cells (myotubes). In order to obtain information on the possible role of individual PKC isozymes in myogenesis, in the present work we investigated the differential expression of PKC isoforms alpha, beta, delta, epsilon, and zeta during muscle cell development in vitro. Chick embryo myoblasts cultured from 1 to 6 days were used as experimental model. Morphological characterization and measurement of specific biochemical parameters in cultures, e.g., DNA synthesis, creatine kinase activity, and myosin levels, revealed a typical muscle cell developmental pattern consisting of an initial proliferation of myoblasts followed by their differentiation into myotubes. PKC activity was high at the proliferation stage, decreased as myoblasts elongated and fused, and increased again in differentiated myotubes. In proliferating myoblasts, the PKC inhibitors calphostin C and bisindolylmaleimide I decreased DNA synthesis whereas in myoblasts undergoing differentiation they exerted the opposite effect, suggesting that PKC plays a role at both stages of myogenesis. Western blot analysis of changes in the expression of PKC isoforms during muscle cell development showed high levels of PKC alpha in the proliferating phase which markedly decreased as myoblasts differentiated. Treatment with TPA of proliferative myoblasts inhibited DNA synthesis and selectively down-regulated PKC alpha, suggesting that this isozyme may have an important role in maintaining myoblast proliferation. On the other hand, an increase in the expression of PKC beta, delta, and epsilon was detected during myogenesis, suggesting that one or more of these isoforms may participate in the differentiation process of myoblasts.

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Section: Discussionsupporting

confidence: 94%

Evidence on the participation of protein kinase C ? in the proliferation of cultured myoblasts

et al. 1999

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“…Since Gö 6976 does not affect novel isoforms, and that inhibitors with low inhibitory potency towards PKCµ (GF109203X and Gö 6983) also suppressed neuroblastoma growth, a conceivable interpretation of is that a classical PKC isoform is of importance for neuroblastoma cell growth. Classical isoforms, particularly PKC␣, have been implicated in growth stimulation and tumor growth in several cell types (Cai et al, 1997;Perletti et al, 1994;Ways et al, 1995) and an antisense oligonucleotide directed towards PKC␣ has been shown to inhibit the growth of several human tumor cell lines in an animal model system (Dean et al, 1996). The facts that PKC␣ and ␤II were found in all neuroblastoma cell lines and neuroblastoma tumors investigated and that the growth suppression by PKC was likely to be due to inhibition of a classical PKC indicate that either PKC␣ or ␤II may be interesting targets for blocking the growth of neuroblastomas.…”

Section: Discussionmentioning

confidence: 99%

Novel and classical protein kinase C isoforms have different functions in proliferation, survival and differentiation of neuroblastoma cells

et al. 1999

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“…Moreover, inhibition of PKC-␣ has been shown to arrest the growth of prostate cancer, hepatoma, and medulloblastoma cell lines (15)(16)(17). LY900003 (Affinitak, ISIS 3521) is the sodium salt of a 20-mer phosphorothioate oligonucleotide that hybridizes to the 3Ј-untranslated region of human PKC-␣ mRNA and inhibits its expression through Rnase-mediated cleavage of hybridized PKC-␣ mRNA (18).…”

Section: Introductionmentioning

confidence: 99%

A Phase I/II Study of LY900003, an Antisense Inhibitor of Protein Kinase C-α, in Combination with Cisplatin and Gemcitabine in Patients with Advanced Non–Small Cell Lung Cancer

Villalona‐Calero

Ritch

Figueroa³

et al. 2004

Clinical Cancer Research

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Purpose: Protein kinase C-␣ has been implicated in malignant transformation and proliferation. Based on in vivo superadditive interaction between the protein kinase C-␣ antisense oligonucleotide LY900003 (Affinitak, ISIS 3521) and cisplatin, we designed this phase I/II trial of LY900003 with cisplatin/gemcitabine Experimental Design: The safety of the combination, as well as potential pharmacokinetic interactions, was evaluated in the phase I portion of the trial. The phase II portion evaluated the antitumor activity of the combination in previously untreated patients with stage IIIB/IV non-small-cell lung cancer (NSCLC).Results: Seven patients received 18 cycles of the combination during the phase I portion. Dose-limiting toxicity was only observed in one of six evaluable patients (grade 3 fatigue). However, due to a relatively high frequency of thrombocytopenia, cisplatin 80 (mg/m 2 ) and gemcitabine (1,000 mg/m 2 ) were recommended for the phase II portion.Antitumor activity was observed in two patients (one with NSCLC and one with pancreatic carcinoma), and prolonged stabilization was observed in two others. No pharmacokinetic interactions occurred. In the phase II portion, 55 NSCLC patients received the combination at two gemcitabine doses [1,000 mg/m 2 , n ‫؍‬ 44 (original cohort); 1,250 mg/m 2 , n ‫؍‬ 11 (expanded cohort)]. Fourteen of 39 evaluable patients in the original cohort had a response rate (1 complete response and 13 partial responses; response, 36%), whereas 2 of 9 evaluable patients in the expanded cohort experienced partial response (combined response rate, 33%). The median time to treatment failure was 3.9 months, whereas the median time response to progression for the 48 patients with evaluable response was 4.4 months (confidence interval, 3.5-5.5 months). Intent to treat median survival time was 8.9 months. Forty-eight percent of the patients experienced catheter-related events.Conclusions: LY900003 can be administered safely in combination with cisplatin and gemcitabine and is associated with antitumor activity in patients with advanced NSCLC. Better characterization of subsets of patients most likely to benefit from this combination therapy is needed.

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Involvement of the α Isoenzyme of Protein Kinase C in the Growth Inhibition Induced by Phorbol Esters in MH1C1 Hepatoma Cells

Cited by 27 publications

References 0 publications

Evidence on the participation of protein kinase C ? in the proliferation of cultured myoblasts

Evidence on the participation of protein kinase C ? in the proliferation of cultured myoblasts

Novel and classical protein kinase C isoforms have different functions in proliferation, survival and differentiation of neuroblastoma cells

A Phase I/II Study of LY900003, an Antisense Inhibitor of Protein Kinase C-α, in Combination with Cisplatin and Gemcitabine in Patients with Advanced Non–Small Cell Lung Cancer

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