An Update on Protein Kinases as Therapeutic Targets—Part I: Protein Kinase C Activation and Its Role in Cancer and Cardiovascular Diseases
Abstract
:1. Introduction
2. The Protein Kinase C (PKC) Family
2.1. Regulation by Lipid Second Messengers
2.2. Regulation by Scaffold Interactions
3. PKC in Cancer
4. PKC in Cardiovascular Diseases
5. PKC in Other Human Diseases
6. Targeting PKC
7. PKC Inhibitors in Clinical Trials
Indication | Compound | Proposed Mechanism | Outcome | Regulatory Status | Refs. |
---|---|---|---|---|---|
Oncology | Bryostatin | Nonselective PKC activator | No benefit | Not approved | [430,431,432,433,434,435,436,437,438,439,440,441,442,443] |
Aprinocarsen | PKCα inhibitor | No benefit | Not approved | [424,427,428,429,444,445] | |
Enzastaurin (LY317615) | PKCβ inhibitor | No benefit | Not approved | [407,409,410,446,447,448,449,450] | |
Tamoxifen | Nonselective PKC inhibitor at high doses, ER inhibitor | Used in the management of many breast and gynecologic cancers; failed trials for other malignancies | Approved | [451,452,453] | |
Midostaurin | Nonselective PKC inhibitor, FLT3 inhibitor | Used in treatment of FLT3-mutated AML | Approved | [454] | |
7-Hydroxystaurosporine (UCN-01) | Nonselective PKC inhibitor, CHK1 inhibitor | No benefit | Not approved | [455,456,457] | |
PMA | Nonspecific PKC activator | No benefit | Not approved | ||
Safingol | PKCβI, PKCδ, and PKCε inhibitor; PI3K inhibitor | No benefit | Not approved | [458,459] | |
12-O-tetradecanoylphorbol-13-acetate | Nonselective PKC activator | No benefit, severe side effects | Not approved | [460] | |
Diabetes mellitus | Ruboxistaurin(LY333531) | PKCβ inhibitor | Improved diabetic retinopathy but not nephropathy in early studies, minimal effect on neuropathy | Not approved | [461,462,463,464,465,466,467,468,469] |
Cardiology | Delcasertib (KAI-9803) | PKCδ inhibitor | No benefit | Not approved | [470,471,472] |
Flosequinan | Nonselective PKC inhibitor | Increased hospitalizations and HF mortality; early study termination | Withdrawn | [422,473] | |
Volatile anesthetics | PKCε activator | Reduced troponin I, inotrope requirements, and length of hospitalization | Approved for other indications | [474,475,476,477,478] | |
Adenosine | PKCε activator | Reduced MI, mortality, vasopressor requirements | Approved for other indications | [479,480,481] | |
Acadesine | PKCε activator, AMPK activator | No reduction in death, MI, or stroke | Not approved | [482,483,484] | |
Bipolar disorder | Endoxifen | Tamoxifen metabolite with four-fold increased PKC inhibition | Improved time to remission | Not approved | [485] |
Nociception | KAI-1678 | Inhibits PKCε translocation | No benefit | Not approved | [486,487] |
Inflammation | Sotrastaurin (AEB071) | Nonselective PKC inhibitor | Worse outcomes in transplant rejection, no benefit in malignancy or autoimmune trials | Not approved | [488,489,490,491] |
Alzheimer’s Disease | Bryostatin | Nonselective PKC activator | Primary endpoint was not significant | Not approved | [492] |
8. Summary
Author Contributions
Funding
Conflicts of Interest
References
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Disease | PKC Isozyme | Associated Pathology |
---|---|---|
Cancer | PKCα | Proliferation; invasion; metastasis; RCC tumor progression; mutated in thyroid cancer; SCC tumorigenesis and progression; elevated in late-stage breast cancer; upregulated in lung cancer; activated in bladder cancer |
PKCβ | Angiogenesis; invasion; elevated in early-stage breast cancer; downregulated in CRC; PKCβII tumor suppressor in CRC; promotes angiogenesis in NHLs and DLBCL | |
PKCδ | Angiogenesis; apoptosis in endometrial cancer; elevated in early-stage breast cancer; downregulated in CRC | |
PKCγ | Increased in CRC | |
PKCε | Oncogene; proliferation; metastasis; chemotherapy resistance; mutated in thyroid cancer; SCC tumorigenesis, progression, and metastasis; keratinocyte cytoskeleton structure; upregulated in lung cancer; downregulated in CRC | |
PKCη | Glioblastoma tumorigenesis; proliferation; radiation resistance; elevated in early-stage breast cancer; upregulated in lung cancer; downregulated in CRC | |
PKCθ | Gastrointestinal stromal tumorigenesis | |
PKCι/λ | Oncogene; upregulated in lung cancer; promotes prostate cancer invasion; conflicting roles in prostate cancer metastasis; elevation associated with poor outcomes in PDAC | |
PKCζ | Elevated in late-stage breast cancer; upregulated in lung cancer; promotes RCC tumor progression | |
Diabetes mellitus | PKCβ | Obesity; glucose transport; insulin resistance; cholesterol and fatty acid metabolism; PKCβII late-stage vascular complications |
PKCδ | Islet cell function | |
Ischemic heart disease | PKCβ | Pathologic postischemic cardiac remodeling |
PKCδ | ROS production; apoptosis; necrosis; postischemic injury | |
PKCε | Mitochondrial function; proteasome function; ALDH2 activation | |
Heart failure | PKCα | Reduced contractility; β-adrenergic receptor uncoupling |
PKCβII | Decreased proteasome function; calcium dysregulation; conflicting roles in hypertrophy; conflicting roles in contractility | |
PKCδ | Abnormal activation in early HF | |
PKCε | Fibrosis; inflammation; depleted in late-stage HF | |
PKCζ | Generation of active NADPH oxidase; Reduced basal and TGF-βI induced fibroblast proliferation; increased MMP1,3,9 release | |
Hypertension | PKCα | Elevated in hypertension |
PKCβ | Elevated in hypertension | |
PKCδ | Elevated in hypertension | |
PKCε | Translocation and increased hypertrophic cellular growth | |
Stroke | PKCδ | Mitochondrial fission; ROS production; blood–brain barrier dysfunction |
PKCε | Cytoprotective; cerebral perfusion | |
Neurodegeneration | PKCδ | Inflammation; neuronal cell death in Parkinson’s; β-amyloid formation in Alzheimer’s disease |
PKCα | Associated with AD, promoting synaptic loss | |
PKCγ | Associated with SCA, promoting neuronal death | |
Bipolar disorder | PKCα | Abnormal gene expression |
PKCε | Abnormal neuronal transmission | |
Nociception | PKCα | Peripheral nociception signaling |
PKCγ | Dorsal root ganglia signal transmission | |
PKCε | Spinal cord signal transmission; peripheral nociception signaling | |
Inflammation | PKCδ | B-cell development; keratinocyte proliferation and dysregulated angiogenesis in psoriasis; eosinophil activation in asthma |
PKCθ | T-cell responses; airway inflammation; joint inflammation | |
PKCζ | Lung inflammation |
Compound Name | Structure | Indication(s) | Target Domain | Mechanism | Isozyme Selectivity |
---|---|---|---|---|---|
Midostaurin | Acute myeloid leukemia | Catalytic domain | Competitive inhibitor of ATP binding site | Multiple protein kinases | |
Riluzole | Amyotrophic lateral sclerosis | Catalytic domain | Competitive inhibitor of ATP binding site | PKCα and other kinases | |
Curcumin | Not approved; used as nutraceutical for ulcerative colitis and other inflammatory conditions | Regulatory domain | C1 inhibitor | PKCα | |
Resveratrol | Not approved; ongoing studies in cancer, cardiovascular disease, neurodegeneration, and aging | Regulatory domain | C1 inhibitor | PKCα; PKCβ; PKCε |
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Silnitsky, S.; Rubin, S.J.S.; Zerihun, M.; Qvit, N. An Update on Protein Kinases as Therapeutic Targets—Part I: Protein Kinase C Activation and Its Role in Cancer and Cardiovascular Diseases. Int. J. Mol. Sci. 2023, 24, 17600. https://doi.org/10.3390/ijms242417600
Silnitsky S, Rubin SJS, Zerihun M, Qvit N. An Update on Protein Kinases as Therapeutic Targets—Part I: Protein Kinase C Activation and Its Role in Cancer and Cardiovascular Diseases. International Journal of Molecular Sciences. 2023; 24(24):17600. https://doi.org/10.3390/ijms242417600
Chicago/Turabian StyleSilnitsky, Shmuel, Samuel J. S. Rubin, Mulate Zerihun, and Nir Qvit. 2023. "An Update on Protein Kinases as Therapeutic Targets—Part I: Protein Kinase C Activation and Its Role in Cancer and Cardiovascular Diseases" International Journal of Molecular Sciences 24, no. 24: 17600. https://doi.org/10.3390/ijms242417600
APA StyleSilnitsky, S., Rubin, S. J. S., Zerihun, M., & Qvit, N. (2023). An Update on Protein Kinases as Therapeutic Targets—Part I: Protein Kinase C Activation and Its Role in Cancer and Cardiovascular Diseases. International Journal of Molecular Sciences, 24(24), 17600. https://doi.org/10.3390/ijms242417600