SKF-96365

SKF-96365 is a TRPC channel antagonist and store-operated calcium entry ( SOCE ) inhibitor. SKF-96365 reduces calcium ion influx by inhibiting the activity and expression of TRPC6, STIM1 and Orai1. SKF-96365 inhibits voltage-gated sodium current (cardiac I Na /NaV1.5 ) and slows myocardial conduction. SKF-96365 inhibits phosphorylation/activation of CaMKIIγ and suppresses the downstream AKT signaling pathway. SKF-96365 induces G 2 /M phase cell cycle arrest, apoptosis and cytoprotective autophagy in colorectal cancer cells. SKF-96365 alleviates allergic rhinitis symptoms by reducing inflammatory cytokine levels. SKF-96365 reduces intracellular calcium overload, inhibits Homer1 expression, prevents nuclear damage and suppresses apoptosis. SKF-96365 inhibits the growth of colorectal cancer xenografts in nude mice. SKF-96365 is applicable to research related to allergic rhinitis, colorectal cancer, Parkinson's disease, persistent spontaneous nociception and hyperalgesia ^{[1] [2] [3] [4] [5]}.

In Vivo, SKF-96365 (200-400 μg; intranasal administration; once daily; for 8 consecutive days) dose-dependently alleviates allergic rhinitis symptoms and suppresses inflammatory responses in BALB/c mice^[1]. SKF-96365 (20 mg/kg; i.p.; once daily for 14 consecutive days) inhibits the growth of colorectal cancer xenografts in athymic BALB/c nude mice by inducing cell cycle arrest, apoptosis and protective autophagy via suppressing the CaMKIIγ/AKT-mediated pathway^[3].

In Vitro, SKF-96365 (0-10 μM; applied until steady-state inhibition is reached) inhibits hNaV1.5 currents stably expressed in HEK 293 cells, with an IC₅₀ of 0.94 μM^[2]. SKF-96365 (0-20 μM) dose-dependently inhibits store-operated calcium entry in human colorectal cancer cell lines HCT116 and HT29^[3]. SKF-96365 (0-40 μM, 48-72 h) inhibits the growth of human colorectal cancer cells HCT116 (IC₅₀ = 10.88 μM) and HT29 (IC₅₀ = 14.56 μM), and exhibits significantly lower toxicity against normal colonic epithelial cells NCM460^[3]. SKF-96365 (0-20 μM, 48 h) induces G2/M cell cycle arrest in human colorectal cancer cells HCT116 and HT29 by regulating key G2/M transition proteins, including upregulating p21waf/Cip1 and downregulating p-Cdc25c, Cdc25c, and Cyclin B^[3]. SKF-96365 (10 μM, 0-24 h) induces apoptosis in human colorectal cancer cell lines HCT116 and HT29 via the endogenous mitochondrial pathway, a process characterized by early (12 h) mitochondrial membrane depolarization, Bax translocation and cytochrome c release, followed by caspase activation and marked apoptosis (24 h)^[3]. SKF-96365 (0-20 μM, 12 h) induces cytoprotective autophagy in human colorectal cancer cells HCT116 and HT29. This effect appears as early as 12 h (prior to apoptosis) and antagonizes apoptosis by sequestering mitochondria into autophagosomes to reduce cytosolic cytochrome c levels^[3]. SKF-96365 (0-20 μM, 24 h) inhibits the AKT/mTOR signaling pathway and the calcium/Ca2+/CaMKIIγ/AKT signaling pathway in human colorectal cancer cell lines HCT116 and HT29^[3]. SKF-96365 (1-50 μM, 24 h) significantly increases the survival rate of PC12 cells treated with MPP+, reduces LDH release, alleviates nuclear damage, membrane damage, and late apoptotic cell death, mitigates intracellular calcium overload, and decreases the mRNA and protein expression levels of Homer1^[4]. SKF-96365 (1-10 µM) inhibits melittin-induced inward currents in acutely isolated small and medium-sized dorsal root ganglion cells of rats in a dose-dependent manner^[5]. SKF-96365 (10 µM) inhibits melittin-induced intracellular Ca2+ elevation, and the proportion of cells exhibiting this inhibitory effect reaches 46.5% in acutely isolated rat dorsal root ganglion cells sensitive to melittin^[5].

References:
[1]. Ba G, et al. Therapeutic effects of SKF-96365 on murine allergic rhinitis induced by OVA. Int J Immunopathol Pharmacol. 2021;35:20587384211015054.
[2]. Chen KH, et al. SKF-96365 strongly inhibits voltage-gated sodium current in rat ventricular myocytes. Pflugers Arch. 2015;467(6):1227-1236.
[3]. Jing Z, et al. SKF-96365 activates cytoprotective autophagy to delay apoptosis in colorectal cancer cells through inhibition of the calcium/CaMKIIγ/AKT-mediated pathway. Cancer Lett. 2016;372(2):226-238.
[4]. Chen T, et al. Protective effects of SKF-96365, a non-specific inhibitor of SOCE, against MPP+-induced cytotoxicity in PC12 cells: potential role of Homer1. PLoS One. 2013;8(1):e55601.
[5]. Ding J, et al. Effects of SKF-96365, a TRPC inhibitor, on melittin-induced inward current and intracellular Ca2+ rise in primary sensory cells. Neurosci Bull. 2011;27(3):135-142.