Role of the Hypoxic Microenvironment in the Antitumor Activity of Tyrosine Kinase Inhibitors

Abstract

The tumor microenvironment is characterized, not only by marked gradients in drug concentration, but also by gradients in the rate of cell proliferation and by regions of hypoxia and acidity, all of which can influence tumor cell sensitivity to drug treatment. Hypoxia is also an important environmental factor in chronic myeloid leukemia (CML), because bone marrow is intrinsically hypoxic in nature. Systems-wide analyses of tumors have recently identified receptor tyrosine kinase coactivation as an important mechanism by which cancer cells achieve chemoresistance. Recent work suggests that Src activation might play a prominent role in the response to hypoxia to promote cell survival, progression, and metastasis of a variety of human cancer. Other studies also established a functional link between Bcr-Abl and the Src family tyrosine kinases. It is well known that mutations can also cause some tyrosine kinases to become constitutively active, a nonstop functional state that may contribute to initiation or progression of cancer as in CML. Leukemic cells carrying chromosomal alteration, are sensitive to imatinib that induces complete remission in most patients. This inhibitor is a highly selective Bcr-Abl tyrosine kinase inhibitor (TKI). There is a considerable interest in understanding how activated signaling pathways enhance tumor cell survival under hypoxia, because this might lead to the introduction of more effective treatments to target these resistant subpopulations. For all these reasons it is important to identify new TKIs which are also active in hypoxia, the real tumor microenvironment, as possible alternative therapy.

Role of RhoB in the Regulation of Pulmonary Endothelial and Smooth Muscle Cell Responses to Hypoxia

“…RhoB is required for the actions of several growth factors induced by hypoxia and regulates endocytotic trafficking of proproliferative and anti-apoptotic kinases Src and Akt. 28,42 There is also evidence that RhoB can activate proinflammatory transcription factor NFkB to much greater extent than RhoA, 24 a fact of potential importance in the regulation of inflammatory responses in the remodeled hypoxic lung. Here we show that the effect of RhoB on HPASMC proliferation is likely to be mediated by PDGF/PDGFR signaling.…”

Antiproliferative effects of masitinib and imatinib against canine oral fibrosarcoma in vitro

“…Some TKIs, such as masitinib, have shown an anticancer action that extends beyond inhibition of its primary targets, and may include disruption of additional signaling pathways associated with tumor progression, metastasis, and chemoresistance [ 25 , 26 , 28 , 29 ]. The in vivo tumor microenvironment is characterized by varying levels of hypoxia and acidity, which influence tumor cell behavior and drug sensitivity, potentially rendering them more or less sensitive to TKI treatment [ 30 ]. PDGFR is emerging as a key regulator of mesenchymal cells within the tumor microenvironment of many common human malignancies [ 31 ].…”

Antileukemic Activity of Sulforaphane in Primary Blasts from Patients Affected by Myelo- and Lympho-Proliferative Disorders and in Hypoxic Conditions

“…Those therapeutic issues can also be imputable to tumor microenvironment, which is characterized not only by marked gradients in drug concentration, but also by regions of hypoxia, which can influence tumor cell sensitivity to drug treatment. Taking into account the intrinsically hypoxic nature of bone marrow, hypoxia is also an important environmental factor in leukemia [26].…”