The colorectal cancer (CRC) is one leading contributor of cancer-related mortality worldwide. The search for effective anti-CRC agents is valuable. In the current study, we showed that icaritin (ICT), an active natural ingredient from the Chinese plant Epimedium, potently inhibited proliferation and survival of established (HT-29, HCT-116, DLD-1, and SW-620) and primary (patient-derived) CRC cells. Significantly, ICT mainly induced necrosis, but not apoptosis, in CRC cells. The necrosis inhibitor necrostatin-1 attenuated ICT-mediated cytotoxicity in CRC cells. We showed that ICT treatment in CRC cells induced mitochondrial permeability transition pore (mPTP) opening, which was evidenced by mitochondrial membrane potential (MMP) decrease and mitochondrial adenine nucleotide translocator-1 (ANT-1)-cyclophilin-D (CyPD) association. On the other hand, mPTP blockers, including sanglifehrin A, cyclosporin A, and bongkrekic acid, as well as siRNA-mediated knockdown of mPTP component (CyPD or ANT-1), significantly alleviated ICT-mediated cytotoxicity against CRC cells. We suggested that Jun-N-terminal kinase (JNK) activation by ICT mediated mPTP opening and subsequent CRC cell necrosis. JNK pharmacological inhibition, dominant negative mutation, or shRNA downregulation suppressed ICT-induced MMP reduction and subsequent HT-29 cell necrosis. In vivo, oral gavage of ICT dramatically inhibited HT-29 xenograft growth in nude mice. The in vivo activity by ICT was largely attenuated by co-administration with the mPTP blocker CsA. Collectively, our results showed that ICT exerts potent inhibitory effect against CRC cells in vitro and in vivo. JNK-dependent mPTP necrosis pathway could be key mechanism responsible for ICT's actions.
The current research studied the potential effect of autophagy on icaritin-induced anti-colorectal cancer (CRC) cell activity. Treatment of icaritin in both primary and established (HT-29) CRC cells induced feedback activation of autophagy, evidenced by p62 degradation, Beclin-1 and autophagy-related gene-5 (ATG-5) upregulation, as well as light chain 3B (LC3B)-GFP puncta formation. Pharmacological inhibiting of autophagy dramatically potentiated icaritin-induced CRC cell death and apoptosis. Meanwhile, shRNA-mediated knockdown of Beclin-1 or ATG-5 also sensitized icaritin-induced CRC cell death and apoptosis. Icaritin activated AMP-activated protein kinase (AMPK) signaling in CRC cells, functioning as the upstream signaling for autophagy activation. shRNA/siRNA-mediated knockdown of AMPKα1inhibited icaritin-induced autophagy activation, but exacerbated CRC cell death. On the other hand, the AMPK activator compound 13 (C13) or the autophagy activator MHY1485 attenuated icaritin-induced cytotoxicity. In nude mice, icaritin (oral administration)-induced HT-29 tumor growth inhibition was potentiated when combined with AMPKα1 shRNA knockdown in tumors. We conclude that feedback activation of AMPK-autophagy pathway could be a primary resistance factor of icaritin.
Abstract. Follicular dendritic cell sarcoma (FDCS), which originates in antigen-presenting cells of the B-cell follicles of the lymph nodes, is an uncommon disease, particularly in a splenic location. In a number of cases, FDCS may easily be confused with other solid tumors and be underdiagnosed. The present study reports a case in which such as tumor occurred in a 64-year-old woman. The patient presented with an abdominal mass, and computed tomography was performed. Histological and immunohistochemical studies revealed a diagnosis of FDCS. The patient underwent surgical treatment and had a good remission. At the time of writing, the patient was in good condition. The present study also discusses the clinical characteristics, treatment methods and prognosis of FDCS, with particular reference to the main points of the imaging diagnosis.
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