Thyroid Hormone and P-Glycoprotein in Tumor Cells

Figure 1

Schematic overview of possible mechanisms in tumor cells by which tetrac and nanotetrac may decrease function or abundance or both of P-gp. Postulated mechanisms are initiated at the thyroid hormone-tetrac receptor site on integrin v3 in the plasma membrane. An example shown is downregulation of the Na⁺/H⁺ antiporter by tetrac that results in decreased intracellular pH (pHi) and increased extracellular pH (pHe), both of which may serve to reduce P-gp function (see text). Another example is inhibition by tetrac of Na, K-ATPase, resulting in increased [Na⁺]_i, reverse mode Na⁺/Ca²⁺ exchange, and increased [Ca²⁺]_i. The latter, in conjunction with calmodulin, can downregulate P-gp activity. EGF is one of several extracellular factors that supports P-gp activity. Tetrac/nanotetrac may remove any contributions of EGF to P-gp activity by disrupting function of the plasma membrane EGF receptor (EGFR) or by decreasing EGFR gene expression. The figure also proposes that the decreased expression of the MDR1 gene is initiated at integrin v3; this possibility has not yet been explored. The figure does not include factors such as osteopontin and VEGF that are also known to regulate P-gp and whose actions might be affected by tetrac/nanotetrac. These factors are discussed in the text.