Carbamoylphosphonates Control Tumor Cell Proliferation and Dissemination by Simultaneously Inhibiting Carbonic Anhydrase IX and Matrix Metalloproteinase-2. Toward Nontoxic Chemotherapy Targeting Tumor Microenvironment

Abstract

Carbamoylphosphonates (CPOs) have been identified as inhibitors of matrix metalloproteinases (MMPs) and as orally active, bioavailable, and safe antimetastatic agents. In this article, we focus on the direct antitumor activity of the CPOs. We discovered that CPOs also inhibit carbonic anhydrases (CAs), especially the IX and XII isoforms identified as cancer promoting factors. Thus, CPOs can be regarded as novel nontoxic drug candidates for tumor microenvironment targeted chemotherapy acting by two synergistic mechanisms, namely, inhibiting CAs and MMPs simultaneously. We have also demonstrated that the ionized CPO acid is unable to cross the cell membrane and thus limited to interact with the extracellular domains of isozymes CAIX and CAXII. Finally, applying CPOs against cancer cells in hypoxic conditions resulted in the dose dependent release of lactate dehydrogenase, confirming the direct interaction of the CPOs with the cancer related isozymes CAIX and XII and thereby promoting cellular damage.

Carbamoylphosphonates inhibit autotaxin and metastasis formationin vivo

“…This is an extension of recently reported research, which showed that CPOs n ¼ 5, 6 -previously recognized in vivo as active anti-metastatic matrix metallo-proteinase (MMP) inhibitors [16][17][18] -also act as CA inhibitors 15 . Matrix metalloproteinases (MMPs) are a family of about 26 zinc endopeptidases, which collectively have the capacity to degrade all the major components of the extracellular matrix.…”

“…MMPs' and CAs' inhibitory constants have been determined as previously described, respectively 15,18 .…”

“…The activity of CAIX is also important for metastasis, as recently demonstrated by Lou et al 14 , who showed that CAIX is an essential factor in the survival of tumor cells in hypoxic areas of breast tumor, and its activity contributes to metastasis generation in breast cancer. Furthermore, both inhibition of CAIX activity and depletion of CAIX expression have been shown to result in regression or growth inhibition of mouse and human breast tumors, as well as inhibition of cancer metastasis 15 .…”

Tumor Microenvironment as Target in Cancer Therapy

“…boronic acids, phosphates and phosphonates, but yielded no in vivo active compounds. 78 As can be seen in Table 17.1, compound 11 is too short to inhibit ATX, but 12 (JS-403) is a potent inhibitor of ATX. Previous work indicated that water solubility for an inhibitor is not enough, because neutral molecules can partition between two phases resulting in inefficient inhibition.…”

Synthesis of Enantiomeric Aminoalkylcarbamoylphosphonates and Their Evaluation as Dual‐Action Anticancer MMP and Carbonic Anhydrase Inhibitors

“…The family of MMPs, discovered decades ago, does not need that much introduction in view of the worldwide (unsuccessful) activity to discover useful inhibitors , not counting our series of recently published carbamoylphosphonate (CPO) MMP inhibitors and one article of CPO CAs .…”