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Oncotarget. 2017 Jul 25;8(30):50187-50192. doi: 10.18632/oncotarget.16238.

Structural homologies between phenformin, lipitor and gleevec aim the same metabolic oncotarget in leukemia and melanoma.

Author information

1
HYD, LLC for Cancer Research & Drug Development, Budapest, Hungary, European Union.
2
CignatureHealth Metabolic Clinic, Santa Monica, CA, USA.
3
EPIGENIX Foundation, El Segundo, CA, USA.
4
The University of Arizona Cancer Center, Tucson, AZ, USA.
5
Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA, USA.
6
Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, Hyperbaric Biomedical Research Laboratory, University of South Florida, Tampa, FL, USA.
7
Department of Pediatrics, University of California Los Angeles School of Medicine, Westwood, CA, USA.
8
Los Angeles Biomedical Research Institute (LABIOMED) at the Harbor-UCLA Medical Center, Torrance, CA, USA.
9
SiDMAP, LLC, Culver City, CA, USA.
10
UCLA Clinical and Translational Science Institute, Torrance, CA, USA.

Abstract

Phenformin's recently demonstrated efficacy in melanoma and Gleevec's demonstrated anti-proliferative action in chronic myeloid leukemia may lie within these drugs' significant pharmacokinetics, pharmacodynamics and structural homologies, which are reviewed herein. Gleevec's success in turning a fatal leukemia into a manageable chronic disease has been trumpeted in medical, economic, political and social circles because it is considered the first successful targeted therapy. Investments have been immense in omics analyses and while in some cases they greatly helped the management of patients, in others targeted therapies failed to achieve clinically stable recurrence-free disease course or to substantially extend survival. Nevertheless protein kinase controlling approaches have persisted despite early warnings that the targeted genomics narrative is overblown. Experimental and clinical observations with Phenformin suggest an alternative explanation for Gleevec's mode of action. Using 13C-guided precise flux measurements, a comparative multiple cell line study demonstrated the drug's downstream impact on submolecular fatty acid processing metabolic events that occurred independent of Gleevec's molecular target. Clinical observations that hyperlipidemia and diabetes are both reversed in mice and in patients taking Gleevec support the drugs' primary metabolic targets by biguanides and statins. This is evident by structural data demonstrating that Gleevec shows pyridine- and phenyl-guanidine homology with Phenformin and identical phenylcarbamoyl structural and ligand binding homology with Lipitor. The misunderstood mechanism of action of Gleevec is emblematic of the pervasive flawed reasoning that genomic analysis will lead to targeted, personalized diagnosis and therapy. The alternative perspective for Gleevec's mode of action may turn oncotargets towards metabolic channel reaction architectures in leukemia and melanoma, as well as in other cancers.

KEYWORDS:

deuterobolomics; imatinib; lipitor; metformin; phenformin

PMID:
28418852
PMCID:
PMC5564842
DOI:
10.18632/oncotarget.16238
[Indexed for MEDLINE]
Free PMC Article

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