Differential Inhibition of Water and Ion Channel Activities of Mammalian Aquaporin-1 by Two Structurally Related Bacopaside Compounds Derived from the Medicinal PlantBacopa monnieri

Abstract

Aquaporin-1 (AQP1) is a major intrinsic protein that facilitates flux of water and other small solutes across cell membranes. In addition to its function as a water channel in maintaining fluid homeostasis, AQP1 also acts as a nonselective cation channel gated by cGMP, a property shown previously to facilitate rapid cell migration in a AQP1-expressing colon cancer cell line. Here we report two new modulators of AQP1 channels, bacopaside I and bacopaside II, isolated from the medicinal plant Bacopa monnieri Screening was conducted in the Xenopus oocyte expression system, using quantitative swelling and two-electrode voltage clamp techniques. Results showed bacopaside I blocked both the water (IC50 117 μM) and ion channel activities of AQP1 but did not alter AQP4 activity, whereas bacopaside II selectively blocked the AQP1 water channel (IC50 18 μM) without impairing the ionic conductance. These results fit with predictions from in silico molecular modeling. Both bacopasides were tested in migration assays using HT29 and SW480 colon cancer cell lines, with high and low levels of AQP1 expression, respectively. Bacopaside I (IC50 48 μM) and bacopaside II (IC50 14 μM) impaired migration of HT29 cells but had minimal effect on SW480 cell migration. Our results are the first to identify differential AQP1 modulators isolated from a medicinal plant. Bacopasides could serve as novel lead compounds for pharmaceutic development of selective aquaporin modulators.

Escin suppresses HMGB1‐induced overexpression of aquaporin‐1 and increased permeability in endothelial cells

“…However, to date few AQP inhibitors have been discovered as suitable candidates for clinical development. Currently, the sulfhydryl‐reactive, heavy metal‐containing compounds and some compounds isolated from medicinal plant have been confirmed as AQP1 inhibitors; however, there is still a need to identify useful inhibitors with therapeutic application in the clinic and limited side effects . In our study, we found a new agent from natural products that can inhibit the expression of AQP1 in a dose‐dependent and time‐dependent manner and improve barrier dysfunction.…”

Fundamental structural and functional properties of Aquaporin ion channels found across the kingdoms of life

“…Block by AqB011 of the AQP1 ionic conductance demonstrated that the cation channel activity is a key component for HT29 cancer cell migration Figure . The continuing evaluation of traditional medicinal plants as sources of blockers of AQP1 has produced agents that selectively inhibit water permeability (such as bacopaside II), or that block both the water and ion channel pores (such as bacopaside I); these also are promising tools for controlling migration in the subset of cancers that rely on AQP1 expression . Bacopaside II isolated from the traditional medicinal herb Bacopa monnieri blocks the migration of cancer cells measured in live‐cell‐imaging assays (Figure ) without toxicity at effective doses …”

“…Highlighted in blue is the loop D domain, in red are the double arginine residues at positions 159 and 160 (R159 + R160) located in the loop D domain. The double arginine site is proposed to be involved in binding of the agonist cGMP and antagonists AqB011 and bacopaside I . Cysteine at position 189 (cyan) is the mercury binding site .…”

Letter to the Editor: “Ion Channels in Brain Metastasis”—Ion Channels in Cancer Set up and Metastatic Progression

“…The role of ion channels in vascular alteration occurring in the metastatic process is clearly recognized but still not completely elucidated, as discussed by Klumpp, L. et al Therefore, we believe that all these ion channels reported by Klumpp, L. et al [1]. , us [2] and others [3,4,5,6,7,8,9] may have a mechanistic role in the primary tumor set up as well as in the metastatic progression toward the brain and other organs.…”

“…For instance, we [2] evaluated the expression of ninety ion-channel genes in 3673 human biopsies, in five different solid tumors (bladder cancer, breast cancer, glioblastoma, lung cancer and melanoma). We [2] and others [3,4,5,6,7,8,9] have shown a key role of ion channels in tumors common to Klumpp, L. et al, namely lung cancer, breast cancer and melanoma, as well as in other cancers such as glioblastoma, bladder cancer and colorectal cancer. These channels are calcium channel voltage-dependent (CACNA1D); FXYD domain-containing ion transport regulators (FXYD3, FXYD5); chloride intracellular channels (CLIC1); glutamate receptors (HTR3A); potassium channel voltage-gated channels (KCNE3, KCNE4, KCNN4); transient receptor potential cation channels (TRPA1, TRPC5, TRPM3, TRPV4) and Aquaporins (AQPs).…”