Thyroid Hormone and P-Glycoprotein in Tumor Cells

Abstract

P-glycoprotein (P-gp; multidrug resistance pump 1, MDR1; ABCB1) is a plasma membrane efflux pump that when activated in cancer cells exports chemotherapeutic agents. Transcription of the P-gp gene (MDR1) and activity of the P-gp protein are known to be affected by thyroid hormone. A cell surface receptor for thyroid hormone on integrin αvβ3 also binds tetraiodothyroacetic acid (tetrac), a derivative of L-thyroxine (T4) that blocks nongenomic actions of T4 and of 3,5,3′-triiodo-L-thyronine (T3) at αvβ3. Covalently bound to a nanoparticle, tetrac as nanotetrac acts at the integrin to increase intracellular residence time of chemotherapeutic agents such as doxorubicin and etoposide that are substrates of P-gp. This action chemosensitizes cancer cells. In this review, we examine possible molecular mechanisms for the inhibitory effect of nanotetrac on P-gp activity. Mechanisms for consideration include cancer cell acidification via action of tetrac/nanotetrac on the Na+/H+ exchanger (NHE1) and hormone analogue effects on calmodulin-dependent processes and on interactions of P-gp with epidermal growth factor (EGF) and osteopontin (OPN), apparently via αvβ3. Intracellular acidification and decreased H+ efflux induced by tetrac/nanotetrac via NHE1 is the most attractive explanation for the actions on P-gp and consequent increase in cancer cell retention of chemotherapeutic agent-ligands of MDR1 protein.

Targeted delivery of paclitaxel and doxorubicin to cancer xenografts via the nanoparticle of nano-diamino-tetrac

“…27 It is possible that the suboptimal dosing of NDAT in the current experiments may have been sufficient to enhance tumor retention time and antitumor efficacy of locally delivered paclitaxel and doxorubicin.…”

“…P-gp is a plasma membrane efflux pump that is a component of cancer cell chemoresistance and is subject to inhibition by tetrac. 26,27 Methods generation of free Plga nanoparticles encapsulated with paclitaxel or doxorubicin…”

Hormony tarczycy w ośrodkowym układzie nerwowym (OUN) i ich wpływ na nowotworzenie, zwłaszcza na rozwój i przebieg glioblastoma multiforme — hipoteza badawcza

“…Recently, P-glycoprotein, also called multidrug resistance protein-P (MDR1), was found in normal cells and particularly in some neoplastic cells, and was suggested to be responsible for the failure of pharmacological treatment. Thyroid hormones were shown to stimulate transcription of the gene for this protein and to affect its activity through integrin receptor [89]. What seems to be most important is the evidence showing that TH signalling can potentiate the EGFR/PTEN/Akt/mTOR pathway, the TP53/MDM2/p14 ARF pathway, the P16/ /RB1 pathway, and the pathway dependent on gene mutation for isocitrate dehydrogenase (IDH) -the signalling generally accepted for the development and clinical course of GBM.…”

Doxorubicin-Loaded Melanin Particles for Enhanced Chemotherapy in Drug-Resistant Anaplastic Thyroid Cancer Cells

“…The standard treatment for this highly aggressive cancer is a combination of doxorubicin (Dox) chemotherapy and radiation therapy [3]. However, malignant ATC cells often develop resistance to Dox, resulting in failure of the treatment [4,5]. Overcoming the drug resistance of cells is therefore essential for improving the prognosis of ATC.…”

“…MDR1 transporters pump Dox molecules out of cells, reducing the intracellular concentration of the drug and inhibiting the chemotherapeutic efficacy [4,7]. Recently, significant effort has been directed towards overcoming the drug resistance of cancer cells using nanoparticles as drug carriers [8,9].…”