Preclinical and Clinical Development of Novel Agents That Target the Protein Kinase C Family

Serova, Maria; Ghoul, Aïda; Benhadji, Karim A.; Cvitkovic, Esteban; Faivre, Sandrine; Calvo, Fabien; Lokiec, François; Raymond, Éric

doi:10.1053/j.seminoncol.2006.04.009

Cited by 64 publications

(43 citation statements)

References 125 publications

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“…NFkB and PKC are both recognized as targets for cancer therapy, [23][24][25] with particular interest in the possible use of NFkB inhibitors to enhance other anti-tumor agents via increased apoptosis. [26][27] Interestingly, other natural compounds and traditional medicines, including resveretrol and curcumin also appear to target Cells were plated in top chambers and grown with specified levels of agents.…”

Section: Discussionmentioning

confidence: 99%

Coix seed extract, A commonly used treatment for cancer in china, inhibits NFκB and protein kinase C signaling

Woo¹,

Li²,

Wilsbach³

et al. 2007

Cancer Biology & Therapy

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A pharmaceutical grade extract of Coix lachryma-jobi seeds is currently the most commonly used treatment for cancer in China. Although clinical data support the use of this preparation of a Traditional Chinese Medicine for cancer treatment, biological basis for the activity of this preparation has not been previously established. To address this issue, we first evaluated the anti-neoplastic activity of a Coix extract emulsion in xenografts of MDA-MB-231 breast cancer cells and found that the extract significantly inhibits growth of MDA-MB-231 xenografts in athymic nude mice. Using oligonucleotide microarrays, we determined that Coix seed extract also significantly affects gene expression in these cells, including downregulation of genes (such as COX-2 and matrixmetalloproteinases) that are considered to be important in neoplasia. The specific gene expression changes noted after Coix seed extract treatment are characteristic of inhibition of NFkB-dependent transcription, leading us to evaluate how the treatment affects that pathway. An NFkBdependent reporter assay demonstrated dose-dependant inhibition of NFkB signaling by treatment of cultures with the extract, and immunofluorescent microscopy found that these effects are associated with reduced translocation of the Rel-A/p65 subunit of NFkB to the nucleus. Coix extract also inhibits activity of protein kinase C, a major mediator of signal transduction and activator of NFkB. Thus, this Traditional Chinese Medicine-based cancer treatment affects cellular pathways of recognized importance in neoplasia.

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Section: Discussionmentioning

confidence: 99%

Coix seed extract, A commonly used treatment for cancer in china, inhibits NFκB and protein kinase C signaling

Woo¹,

Li²,

Wilsbach³

et al. 2007

Cancer Biology & Therapy

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“…Another PKC inhibitor is enzastaurin, which targets not only PKCβ but also other kinases (20). This multi-kinase inhibitor and other less selective PKC inhibitors are currently in early phase I trials in oncology (21).…”

Section: Figurementioning

confidence: 99%

The PKC inhibitor AEB071 may be a therapeutic option for psoriasis

Skvara

Dawid²,

Kleyn³

et al. 2008

J. Clin. Invest.

153

139

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PKC isoforms t, α, and β play fundamental roles in the activation of T cells and other immune cell functions.Here we show that the PKC inhibitor AEB071 both abolishes the production of several cytokines by activated human T cells, keratinocytes, and macrophages in vitro and inhibits an acute allergic contact dermatitis response in rats. To translate these findings into humans, single and multiple ascending oral doses of AEB071 were administered to healthy volunteers and patients with psoriasis, respectively. AEB071 was well tolerated with no clinically relevant laboratory abnormalities. Ex vivo stimulation of lymphocytes from subjects exposed to single doses of AEB071 resulted in a dose-dependent inhibition of both lymphocyte proliferation and IL2 mRNA expression. Clinical severity of psoriasis was reduced up to 69% compared with baseline after 2 weeks of treatment, as measured by the Psoriasis Area Severity Index (PASI) score. The improvement in psoriasis patients was accompanied by histological improvement of skin lesions and may be partially explained by a substantial reduction of p40 + dermal cells, which are known to mediate psoriasis. These data suggest that AEB071 could be an effective novel treatment regimen for psoriasis and other autoimmune diseases, and that AEB071 warrants long-term studies to establish safety and efficacy.

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“…Protein kinases C have been shown to play an important role in a variety of cellular events, including cellular proliferation, cell cycle progression, differentiation, drug efflux, apoptosis, and tumour angiogenesis (Serova et al, 2006). Evidence has suggested that selective targeting of PKC may enhance the therapeutic efficacy of established chemotherapeutic agents and sensitise cancer cells to ionising radiation (Mackay and Twelves, 2007).…”

mentioning

confidence: 99%

Antiproliferative activity of PEP005, a novel ingenol angelate that modulates PKC functions, alone and in combination with cytotoxic agents in human colon cancer cells

et al. 2008

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PEP005 is a novel ingenol angelate that modulates protein kinases C (PKC) functions by activating PKCd and inhibiting PKCa. This study assessed the antiproliferative effects of PEP005 alone and in combination with several other anticancer agents in a panel of 10 human cancer cell lines characterised for expression of several PKC isoforms. PEP005 displayed antiproliferative effects at clinically relevant concentrations with a unique cytotoxicity profile that differs from that of most other investigated cytotoxic agents, including staurosporine. In a subset of colon cancer cells, the IC 50 of PEP005 ranged from 0.01 -140 mM. The antiproliferative effects of PEP005 were shown to be concentration-and time-dependent. In Colo205 cells, apoptosis induction was observed at concentrations ranging from 0.03 to 3 mM. Exposure to PEP005 also induced accumulation of cells in the G1 phase of the cell cycle. In addition, PEP005 increased the phosphorylation of PKCd and p38. In Colo205 cells, combinations of PEP005 with several cytotoxic agents including oxaliplatin, SN38, 5FU, gemcitabine, doxorubicin, vinorelbine, and docetaxel yielded sequence-dependent antiproliferative effects. Cell cycle blockage induced by PEP005 in late G1 lasted for up to 24 h and therefore a 24 h lag-time between PEP005 and subsequent exposure to cytotoxics was required to optimise PEP005 combinations with several anticancer agents. These data support further evaluation of PEP005 as an anticancer agent and may help to optimise clinical trials with PEP005-based combinations in patients with solid tumours.

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Preclinical and Clinical Development of Novel Agents That Target the Protein Kinase C Family

Cited by 64 publications

References 125 publications

Coix seed extract, A commonly used treatment for cancer in china, inhibits NFκB and protein kinase C signaling

Coix seed extract, A commonly used treatment for cancer in china, inhibits NFκB and protein kinase C signaling

The PKC inhibitor AEB071 may be a therapeutic option for psoriasis

Antiproliferative activity of PEP005, a novel ingenol angelate that modulates PKC functions, alone and in combination with cytotoxic agents in human colon cancer cells

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