• Biomolecules & Therapeutics
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• 제30권6호
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• pp.553-561
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• 2022

Chronic myeloid leukemia (CML) is a slowly progressing hematopoietic cell disorder. Sphingosine kinase 1 (SPHK1) plays established roles in tumor initiation, progression, and chemotherapy resistance in a wide range of cancers, including leukemia. However, small-molecule inhibitors targeting SPHK1 in CML still need to be developed. This study revealed the role of SPHK1 in CML and investigated the potential anti-leukemic activity of hirsuteine (HST), an indole alkaloid obtained from the oriental plant Uncaria rhynchophylla, in CML cells. These results suggest that SPHK1 is highly expressed in CML cells and that overexpression of SPHK1 represents poor clinical outcomes in CML patients. HST exposure led to G2/M phase arrest, cellular apoptosis, and downregulation of Cyclin B1 and CDC2 and cleavage of Caspase 3 and PARP in CML cells. HST shifted sphingolipid rheostat from sphingosine 1-phosphate (S1P) towards the ceramide coupled with a marked inhibition of SPHK1. Mechanistically, HST significantly blocked SPHK1/S1P/S1PR1 and BCR-ABL/PI3K/Akt pathways. In addition, HST can be docked with residues of SPHK1 and shifts the SPHK1 melting curve, indicating the potential protein-ligand interactions between SPHK1 and HST in both CML cells. SPHK1 overexpression impaired apoptosis and proliferation of CML cells induced by HST alone. These results suggest that HST, which may serve as a novel and specific SPHK1 inhibitor, exerts anti-leukemic activity by inhibiting the SPHK1/S1P/S1PR1 and BCR-ABL/PI3K/Akt pathways in CML cells, thus conferring HST as a promising anti-leukemic drug for CML therapy in the future.

• Korean Journal of Plant Resources
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• 제33권4호
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• pp.279-286
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• 2020

Purple loosestrife-Lythrum anceps (Koehne) Makino is a herbaceous perennial plant belonging to the Lythraceae family. It has been used for centuries in Korea and other Asian traditional medicine. It has been showed pharmacological effects, including anti-oxidant and anti-microbial effects. However, the mechanisms underlying its anti-cancer effect are not yet understood. In this study, we investigated the mechanism of apoptosis signaling pathways by ethanol extract of Lythrum anceps (Koehne) Makino (ELM) in human leukemia U937 cells. Treatment with ELM significantly inhibited cell growth in a dose-dependent manner by inducing apoptosis, as evidenced by the formation of apoptotic bodies (ApoBDs), DNA fragmentation and increased populations of sub-G1 ratio. Induction of apoptosis by ELM was connected with up-regulation of death receptor (DR) 4 and DR5, pro-apoptotic Bax protein expression and down-regulation of anti-apoptotic Bcl-2 protein, and inhibitor of apoptosis protein (IAP) family proteins, depending on dosage. This induction was associated with Bid truncation, mitochondrial dysfunction, proteolytic activation of caspases (-3, -8 and -9) and cleavage of poly(ADP-ribose) polymerase protein. Therefore, our data indicate that ELM suppresses U937 cell growth by activating the intrinsic and extrinsic apoptosis pathways, and thus may have applications as a potential source for an anti-leukemic chemotherapeutic agent.

• Journal of Life Science
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• 제18권1호
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• pp.120-128
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• 2008

The death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/ Apo1L is a cytokine that activates apoptosis through cell surface death receptors. TRAIL has sparked growing interest in oncology due to its reported ability to selectively trigger cancer cell death. Euphorbiae humifusae Wind has been used in traditional Oriental medicine as a folk remedy used for the treatment of cancer. However, the mechanism responsible for the anticancer effects of E. humifusae not clearly understood. Here, we show that treatment with subtoxic doses of water extract of E. humifusae (WEEH) in combination with TRAIL induces apoptosis in TRAIL-resistant human gastric carcinoma AGS cells. Combined treatment with WEEH and TRAIL induced chromatin condensation and sub-G1 phase DNA content. These indicators of apoptosis were correlated with the induction of caspase activity that resulted in the cleavage of poly (ADP-ribose) polymerase. Combined treatment also triggered the loss of mitochondrial membrane potential. Furthermore, co-treatment with WEEH and TRAIL down-regulated the protein levels of the anti-apoptotic proteins such as Bcl-2, Bcl-xL, XIAP and cIAP-1. Although more study will be needed to examine the detailed mechanisms, this combined treatment may offer an attractive strategy for safely treating gastric adenocarcinomas and the results provide important new insights into the possible molecular mechanisms of the anticancer activity of E. humifusae.

• Korean Journal of Food Science and Technology
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• 제40권2호
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• pp.207-214
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• 2008

In Asia Saussurea lappa (SL) has been used as a traditional herbal medicine to treat abdominal pain and tenesmus. Recently, in vitro cell culture studies have shown that SL has anti-ulcer, anti-inflammatory, and anti-tumor properties. To explore its potential chemopreventive and chemotherapeutic effects in colon cancer, we examined whether the hexane extract of SL (HESL) could inhibit the growth of HT-29 human colon cancer cells, and investigated the mechanisms for this effect. The cells were cultured with various concentrations (0-5 ${\mu}g/mL$) of HESL. The results indicated that HESL markedly decreased the numbers of viable HT-29 cells; whereas at the concentration of 5 ${\mu}g/mL$, HESL slightly decreased the viable cell numbers of CCD 1108Sk human skin normal fibroblasts at 72 hr. HESL substantially increased the numbers of cells in the sub G1 phase, and dose-dependently increased apoptotic cell numbers. Western blot analysis of the total cell lysates revealed that HESL increased Bax protein levels, but did not affect Bcl-2 levels. HESL induced the cleavage of poly (ADP-ribose) polymerase and caspases 8, 9, 7, and 3. This study demonstrated that HESL inhibits cell growth and induces apoptosis in HT-29 cells, which may be mediated by its ability to increase Bax levels and activate the caspase pathway. These findings may lead to the development of new therapeutic strategies for colon cancer treatment.