ABSTRACT
BACKGROUND AND PURPOSE: Gastrointestinal tumours overexpress voltage-gated calcium (CaV3) channels (CaV3.1, 3.2 and 3.3). CaV3 channels regulate cell growth and apoptosis colorectal cancer. Gossypol, a polyphenolic aldehyde found in the cotton plant, has anti-tumour properties and inhibits CaV3 currents. A systematic study was performed on gossypol blocking mechanism on CaV3 channels and its potential anticancer effects in colon cancer cells, which express CaV3 isoforms. EXPERIMENTAL APPROACH: Transcripts for CaV3 proteins were analysed in gastrointestinal cancers using public repositories and in human colorectal cancer cell lines HCT116, SW480 and SW620. The gossypol blocking mechanism on CaV3 channels was investigated by combining heterologous expression systems and patch-clamp experiments. The anti-tumoural properties of gossypol were estimated by cell proliferation, viability and cell cycle assays. Ca2+ dynamics were evaluated with cytosolic and endoplasmic reticulum (ER) Ca2+ indicators. KEY RESULTS: High levels of CaV3 transcripts correlate with poor prognosis in gastrointestinal cancers. Gossypol blockade of CaV3 isoforms is concentration- and use-dependent interacting with the closed, activated and inactivated conformations of CaV3 channels. Gossypol and CaV3 channels down-regulation inhibit colorectal cancer cell proliferation by arresting cell cycles at the G0/G1 and G2/M phases, respectively. CaV3 channels underlie the vectorial Ca2+ uptake by endoplasmic reticulum in colorectal cancer cells. CONCLUSION AND IMPLICATIONS: Gossypol differentially blocked CaV3 channel and its anticancer activity was correlated with high levels of CaV3.1 and CaV3.2 in colorectal cancer cells. The CaV3 regulates cell proliferation and Ca2+ dynamics in colorectal cancer cells. Understanding this blocking mechanism maybe improve cancer therapies.
Subject(s)
Calcium Channel Blockers , Calcium Channels, T-Type , Cell Proliferation , Colonic Neoplasms , Gossypol , Humans , Gossypol/pharmacology , Gossypol/analogs & derivatives , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Colonic Neoplasms/metabolism , Calcium Channel Blockers/pharmacology , Cell Proliferation/drug effects , Calcium Channels, T-Type/metabolism , Calcium Channels, T-Type/genetics , G1 Phase Cell Cycle Checkpoints/drug effects , Calcium/metabolism , Cell Line, Tumor , Resting Phase, Cell Cycle/drug effects , Antineoplastic Agents/pharmacologyABSTRACT
One of the most broadly used models for membrane fouling is the Hermia model (HM), which separates this phenomenon into four blocking mechanisms, each with an associated parameter n. The original model is given by an Ordinary Differential Equation (ODE) dependent on n. This ODE is solved only for these four values of n, which limits the effectiveness of the model when adjusted to experimental data. This paper aims extend the original Hermia model to new values of n by slightly increasing the complexity of the HM while keeping it as simple as possible. The extended Hermia model (EHM) is given by a power law for any n ≠ 2 and by an exponential function at n = 2. Analytical expressions for the fouling layer thickness and the accumulated volume are also obtained. To better test the model, we perform model fitting of the EHM and compare its performance to the original four pore-blocking mechanisms in six micro- and ultrafiltration examples. In all examples, the EHM performs consistently better than the four original pore-blocking mechanisms. Changes in the blocking mechanisms concerning transmembrane pressure (TMP), crossflow rate (CFR), crossflow velocity (CFV), membrane composition, and pretreatments are also discussed.