METFORMIN SHOULD BE GIVEN WHENEVER ERLOTINIB IS GIVEN, TO SILENCE EGFR AND IGF CROSS-TALK

METFORMIN SHOULD BE GIVEN WHENEVER ERLOTINIB IS GIVEN, TO SILENCE  EGFR AND IGF CROSS-TALK
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WIKIPEDIA

"Role in cancer

The IGF-1R is implicated in several cancers,^[4][5] including breast, prostate, and lung cancers. In some instances its anti-apoptotic properties allow cancerous cells to resist the cytotoxic properties of chemotherapeutic drugs or radiotherapy. In breast cancer, where EGFR inhibitors such as erlotinib are being used to inhibit the EGFR signaling pathway, IGF-1R confers resistance by forming one half of a heterodimer (see the description of EGFR signal transduction in the erlotinib page), allowing EGFR signaling to resume in the presence of a suitable inhibitor. This process is referred to as crosstalk between EGFR and IGF-1R. It is further implicated in breast cancer by increasing the metastatic potential of the original tumour by inferring the ability to promote vascularisation.
Increased levels of the IGF-IR are expressed in the majority of primary and metastatic prostate cancer patient tumors.^[6] Evidence suggests that IGF-IR signaling is required for survival and growth when prostate cancer cells progress to androgen independence.^[7] In addition, when immortalized prostate cancer cells mimicking advanced disease are treated with the IGF-1R ligand, IGF-1, the cells become more motile.^[8] Members of the IGF receptor family and their ligands also seem to be involved in the carcinogenesis of mammary tumors of dogs.^{[9][10]"
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MOST OF OUR PATIENTS ARE OBESE, WE CAN EITHER MEASURE THE IGF OR ASSUME THAT OBESE PATIENT HAVE SOME INSULIN RECEPTOR RESISTANCE, AND THEREFORE MUST HAVE A RELATIVELY HIGH INSULIN, AND THEREFORE SOME METFORMIN WILL BE SAFE TO ADMINISTER.
WITH THE BROAD USE OF INSULIN, THE PERCEPTION IS THAT THIS WILL BE SAFE TO ADMINISTER.  TOLERANCE OF ERLOTINIB AND SIDE EFFECT PROFILE MAY ALSO SUGGEST, THE COMBINATION MAY BE EASILY TOLERATED!
PROOF OF CONCEPT WILL BE HOWEVER ESTABLISH THAT REDUCING CROSS TALK MAY MAXIMIZE ERLOTINIB EFFECTIVENESS!  REMEMBER METFORMIN HAS ITS OWN ANTIPROLIFERATIVE EFFECT!  A WIN-WIN SITUATION THAT WILL PROVE SYNERGY!
CAUTION: SIDE EFFECTS ARE UNKNOWN UNTIL A FORMAL TRIAL-DON'T DO THIS ON YOUR OWN!
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A GOOD TRIAL THOUGH SHOULD REPORT OR TRACK THE STATUS OF CAVEOLIN-1  THOUGH}

Caveolin-1 is essential for metformin inhibitory effect on IGF1 action in non-small-cell lung cancer cells.

Salani B, Maffioli S, Hamoudane M, Parodi A, Ravera S, Passalacqua M, Alama A, Nhiri M, Cordera R, Maggi D.

Source

Department of Endocrinology and Medicine, University of Genoa, Genoa, Italy.

Abstract

Metformin causes an AMP/ATP ratio increase and AMP-activated protein kinase (AMPK) activation. Since caveolin-1 (Cav-1) plays a role in AMPK activation and energy balance, we investigated whether Cav-1 could participate in metformin's inhibitory effect on IGF1 signaling. The effect of metformin was studied in two non-small-cell lung cancer (NSCLC) cell lines, Calu-1 and Calu-6, expressing higher and lower amounts of Cav-1, respectively. In Calu-1, but not in Calu-6 cells, metformin reduced phosphorylation of type 1 insulin-like growth factor receptor (IGF-IR) substrates Akt and Forkhead transcription factor 3a (FOXO3a), inhibited IGF1-dependent FOXO3a nuclear exit, and decreased IGF1-dependent cell proliferation. Here, we show that sensitivity of NSCLC cells to metformin was dependent on Cav-1 expression and that metformin required Cav-1 to induce AMPK phosphorylation and AMP/ATP ratio increase. Cav-1 silencing in Calu-1 and overexpression in Calu-6 reduced and improved, respectively, the inhibitory effect of metformin on IGF1-dependent Akt phosphorylation. Prolonged metformin treatment in Calu-6 cells induced a dose-dependent expression increase of Cav-1 and OCT1, a metformin transporter. Cav-1 and OCT1 expression was associated with the antiproliferative effect of metformin in Calu-6 cells (IC(50)=18 mM). In summary, these data suggest that Cav-1 is required for metformin action in NSCLC cells.

PMID:

22038047

[PubMed