Targeted inhibition of phosphatidyl inositol-3-kinase p110β, but not p110α, enhances apoptosis and sensitivity to paclitaxel in chemoresistant ovarian cancers

Jeong, Jooyeon; Kim, Kyung-Sul; Moon, Jisook; Song, Ji-ae; Choi, Sangjoon; Kim, Kwang Il; Kim, Tae-Heon; An, Hee-Jung

doi:10.1007/s10495-013-0807-9

Cited by 25 publications

(20 citation statements)

References 36 publications

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“…PTX can arrest the cell cycle in G 0 /G 1 or G 2 /M phases and subsequently induce apoptosis of cancer cells. 13,14 It exhibits significant therapeutic capability for various types of cancers, including human ovarian cancer, 15,16 breast cancer, 17 gastric cancer 13 and other malignancies. 14 As well as its anti-cancer activity, PTX has been shown to adjust fibrogenic signaling and inflammatory responses.…”

Section: Introductionmentioning

confidence: 99%

<p>Improving the anti-keloid outcomes through liposomes loading paclitaxel–cholesterol complexes</p>

Wang

Chen

Huang

et al. 2019

IJN

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Background: Keloids represent benign fibroproliferative tumors which result from elevated expression of inflammation. Paclitaxel (PTX) was an effective chemotherapeutic agent and has been reported to have anti-fibrotic effects, but the strong hydrophobicity brings a challenge for its clinical application. Purpose: The objective of this study was to improve the water solubility of PTX and investigate its anti-keloid effects. Methods: We prepared a PTX-cholesterol-loaded liposomes (PTXL) by thin film evaporation fashion and characterized their physicochemical properties. We also investigated the effects of PTX on proliferation, invasion and fibrosis of keloid fibroblasts in vitro and in vivo. Results: The prepared PTXL have a spherical appearance, a particle size of 101.43 nm and a zeta potential of-41.63 mV. PTXL possessed a high drug entrapment efficiency of 95.63% and exhibited a good stability within 30 days. The drugs in PTXL were released in a slow and sustained mode. The PTXL could be effectively uptaken into human keloids fibroblast (HKFs) in a time-dependent manner. In vitro, PTXL showed better ability on inhibiting cell proliferation, migration and invasion, and effectively on promoting apoptosis and arresting cell cycle in G 2 /M phase compared to PTX. Meanwhile, in vivo studies indicated that the PTXL had better performance on inhibiting the keloids growth compared to the PTX in keloid-bearing BALB/c nude mice model. Finally, we found PTX treatment suppressed the production of tumor necrosis factor alpah (TNF-α), interleukin 6 (IL-6) and transforming growth factor beta (TGF-β) and inhibited the expression of alpha smooth muscle actin (α-SMA) and collagen I in HKFs. The activation of protein kinase B (AKT)/glycogen synthase kinase 3 beta (GSK3β) signaling pathway also blocked by PTX in cultured HKFs and keloid tissues. LY294002, a PI3K (phosphatidylinositol 3-kinase)/AKT inhibitor, also suppressed the expression of TNF-α, IL-6 and TGF-β, and simultaneously, reduced the production of α-SMA and collagen I in HKFs. The inhibition of AKT/GSK3β signaling pathway contribute to inhibit the generation of fibrogenic cytokines by PTXL on ameliorating fibrosis progress in keloids. Conclusion: Our results suggested that the developed PTXL would become a promising therapeutic agent in the field of anti-keloid therapy.

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Section: Introductionmentioning

confidence: 99%

<p>Improving the anti-keloid outcomes through liposomes loading paclitaxel–cholesterol complexes</p>

Wang

Chen

Huang

et al. 2019

IJN

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“…Over-representation of the PIK3CA gene is one of the most frequently reported abnormalities in ovarian carcinogenesis and is thought to be an early event (13). The p110β isoform is also significantly overexpressed both in ovarian cancer patients and paclitaxel-resistant ovarian cancer cell lines (14). However, whether TLR-mediated PI3K-dependent signaling is correlated with invasive capacity dependent of cancer stage…”

Section: Introductionmentioning

confidence: 99%

Induction of galectin-1 by TLR-dependent PI3K activation enhances epithelial-mesenchymal transition of metastatic ovarian cancer cells

2017

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The expression of different toll-like receptors (TLRs) on tumor cells has been associated with disease aggressiveness, treatment resistance, and poor prognosis. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is considered critical for cancer cell survival and proliferation. Thus, we investigated the effect of TLR-stimulated PI3K activation on the epithelial-to-mesenchymal transition (EMT) of primary (Caov-3) and metastatic (SK‑OV‑3) epithelial ovarian cancer cell lines in this study. TLR engagement with various ligands promoted the expression of class IA PI3K (p110α, p110β, and p110δ) and increased the expression of mesenchymal markers (N-cadherin, Slug, Vimentin, Snail, α-SMA, and TCF) in SK‑OV‑3 cells. The migratory activity and secretion of EMT-related cytokines of SK‑OV‑3 were significantly higher compared to those of Caov-3 after activation with TLR agonist. Although the invasive capacity and production of EMT-related cytokines of LPS-stimulated SK‑OV‑3 cells were significantly suppressed by all pharmacological inhibitors of the p110 isoform, the Syk/Src-dependent p110β isoform prominently attenuated migration activity. In contrast, the production of IL-10 and galectin-1 was mainly affected by the p110δ isoform. Gene silencing of TLR4 and galectin-1 with siRNA decreased the expression of matrix metalloproteinase-2 (MMP2) and MMP9 and reduced mesenchymal markers in LPS-treated SK‑OV‑3 cells. This study demonstrated that TLR-mediated PI3K activation modulated the invasion and metastasis of ovarian cancer through the production of galectin-1, suggesting that inhibition of the p110 isoform is a promising therapeutic approach against metastatic ovarian cancer.

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“…However, in other tumor entities, such as gastric cancer and non-small cell lung cancer, siRNA-mediated knockdown of BCL2 and XIAP, respectively, induced apoptosis and reduced tumor growth [24,25]. Likewise, even though the phosphatidylinositol 3-kinase (PI3K) p110 isoforms α and β are both upregulated in paclitaxel-resistant ovarian cancer cells only the siRNA-mediated knockdown of PI3K p110β resensitized these cells towards paclitaxel [26]. …”

Section: Resultsmentioning

confidence: 99%

Enhanced Inhibition of Bladder Cancer Cell Growth by Simultaneous Knockdown of Antiapoptotic Bcl-xL and Survivin in Combination with Chemotherapy

Kunze

Erdmann

Froehner

et al. 2013

IJMS

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The overexpression of antiapoptotic genes, such as Bcl-xL and survivin, contributes to the increased survival of tumor cells and to the development of treatment resistances. In the bladder cancer cell lines EJ28 and J82, the siRNA-mediated knockdown of survivin reduces cell proliferation and the inhibition of Bcl-xL sensitizes these cells towards subsequent chemotherapy with mitomycin C and cisplatin. Therefore, the aim of this study was to analyze if the simultaneous knockdown of Bcl-xL and survivin might represent a more powerful treatment option for bladder cancer than the single inhibition of one of these target genes. At 96 h after transfection, reduction in cell viability was stronger after simultaneous inhibition of Bcl-xL and survivin (decrease of 40%–48%) in comparison to the single target treatments (decrease of 29% at best). Furthermore, simultaneous knockdown of Bcl-xL and survivin considerably increased the efficacy of subsequent chemotherapy. For example, cellular viability of EJ28 cells decreased to 6% in consequence of Bcl-xL and survivin inhibition plus cisplatin treatment whereas single target siRNA plus chemotherapy treatments mediated reductions down to 15%–36% only. In conclusion, the combination of simultaneous siRNA-mediated knockdown of antiapoptotic Bcl-xL and survivin—a multitarget molecular-based therapy—and conventional chemotherapy shows great potential for improving bladder cancer treatment.

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Targeted inhibition of phosphatidyl inositol-3-kinase p110β, but not p110α, enhances apoptosis and sensitivity to paclitaxel in chemoresistant ovarian cancers

Cited by 25 publications

References 36 publications

<p>Improving the anti-keloid outcomes through liposomes loading paclitaxel–cholesterol complexes</p>

<p>Improving the anti-keloid outcomes through liposomes loading paclitaxel–cholesterol complexes</p>

Induction of galectin-1 by TLR-dependent PI3K activation enhances epithelial-mesenchymal transition of metastatic ovarian cancer cells

Enhanced Inhibition of Bladder Cancer Cell Growth by Simultaneous Knockdown of Antiapoptotic Bcl-xL and Survivin in Combination with Chemotherapy

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Targeted inhibition of phosphatidyl inositol-3-kinase p110β, but not p110α, enhances apoptosis and sensitivity to paclitaxel in chemoresistant ovarian cancers

Cited by 25 publications

References 36 publications

<p>Improving the anti-keloid outcomes through liposomes loading paclitaxel&ndash;cholesterol complexes</p>

<p>Improving the anti-keloid outcomes through liposomes loading paclitaxel&ndash;cholesterol complexes</p>

Induction of galectin-1 by TLR-dependent PI3K activation enhances epithelial-mesenchymal transition of metastatic ovarian cancer cells

Enhanced Inhibition of Bladder Cancer Cell Growth by Simultaneous Knockdown of Antiapoptotic Bcl-xL and Survivin in Combination with Chemotherapy

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<p>Improving the anti-keloid outcomes through liposomes loading paclitaxel–cholesterol complexes</p>

<p>Improving the anti-keloid outcomes through liposomes loading paclitaxel–cholesterol complexes</p>