Therapeutic targeting of Neu1 sialidase with oseltamivir phosphate (Tamiflu®) disables cancer cell survival in human pancreatic cancer with acquired chemoresistance

Abstract

Background:Resistance to drug therapy, along with high rates of metastasis, contributes to the low survival rate in patients diagnosed with pancreatic cancer. An alternate treatment for human pancreatic cancer involving targeting of Neu1 sialidase with oseltamivir phosphate (Tamiflu ® ) was investigated in human pancreatic cancer (PANC1) cells with acquired resistance to cisplatin and gemcitabine. Its efficacy in overcoming the intrinsic resistance of the cell to chemotherapeutics and metastasis was evaluated. Methods: Microscopic imaging, immunocytochemistry, immunohistochemistry, and WST-1 cell viability assays were used to evaluate cell survival, morphologic changes, and expression levels of E-cadherin, N-cadherin, and VE-cadherin before and after treatment with oseltamivir phosphate in PANC1 cells with established resistance to cisplatin, gemcitabine, or a combination of the two agents, and in archived paraffin-embedded PANC1 tumors grown in RAGxCγ double mutant mice. Results: Oseltamivir phosphate overcame the chemoresistance of PANC1 to cisplatin and gemcitabine alone or in combination in a dose-dependent manner, and disabled the cancer cell survival mechanism(s). Oseltamivir phosphate also reversed the epithelial-mesenchymal transition characteristic of the phenotypic E-cadherin to N-cadherin changes associated with resistance to drug therapy. Low-dose oseltamivir phosphate alone or in combination with gemcitabine in heterotopic xenografts of PANC1 tumors growing in RAGxCγ double mutant mice did not prevent metastatic spread to the liver and lung. Conclusion: Therapeutic targeting of Neu1 sialidase with oseltamivir phosphate at the growth factor receptor level disables the intrinsic signaling platform for cancer cell survival in human pancreatic cancer with acquired chemoresistance. These findings provide evidence for oseltamivir phosphate (Tamiflu) as a potential therapeutic agent for pancreatic cancer resistant to drug therapy.

Neuraminidase-1: A novel therapeutic target in multistage tumorigenesis

“…It follows that the therapeutic efficacy of oseltamivir phosphate targeting Neu1 may disrupt these molecular signaling pathways. Given the ability of oseltamivir phosphate to increase E-cadherin expression and decrease N-cadherin and VE-cadherin expression as previously reported by us [46], tumors treated with this drug may become more adherent to the surrounding tissue and not metastasize as our data indicated. We propose here a graphical abstract (Figure 2) illustrating that the Snail-MMP9 signaling axis maintains several important cancer growth factor receptor signaling platforms in promoting Neu1-MMP9 crosstalk in complex with glycosylated receptors.…”

“…Indeed, the desialylation activity of Neu1 has been shown to regulate cancer growth, and its selective inhibition has demonstrated significant therapeutic results in murine models of cancer. Neu1 inhibition by oseltamivir phosphate has been shown to specifically increase E-cadherin expression and to decrease N-cadherin expression in pancreatic cancer [30, 46], triple-negative breast cancer [112] and in ovarian tumor models [206]. This shift in E- and N-cadherin expression may obstruct the occurrence of EMT in drug-resistant phenotypes, prevent cancer cell metastases, and improve the drug sensitivity of chemoresistant cells.…”

“…We have reported that chronic treatment of human pancreatic PANC1 cancer cells with 0.01μM gemcitabine, 80μM cisplatin, or in their combination resulted in characteristic morphological changes with increased spindle shape morphology and cellular projections [46]. In addition, there were clear molecular alterations involving increased expressions of N- and VE-cadherin and a decreased expression of E-cadherin.…”

Sialylation facilitates self-assembly of 3D multicellular prostaspheres by using cyclo-RGDfK(TPP) peptide

“…It is proposed that this process is initiated by the desialylation of receptor tyrosine kinase. It has been reported that OP has anti-cancer activity against pancreatic, ovarian, and triple-negative breast cancer cell types 48,75. OP has been shown to inhibit the Neu1 sialidase activity of LPS-stimulated BMC2 macrophage cells60 and EGF-stimulated PANC1 cells 59.…”

“…Neu hydrolyzes terminal N- or 0-acylneuraminic acids which are α2,6-, α2,3-, or α2,8-linked (rate: α2,6>α2,3>α2,8) to glycoconjugates. Oseltamivir phosphate (OP) solution was prepared by dissolving 75 mg Tamiflu (Hoffman-La Roche Ltd., Basel, Switzerland) capsule in sterile 1× phosphate-buffered saline (PBS) followed by centrifugation at 1,000 rpm for 10 minutes 48. The stock extracted OP at 20 mg/mL was characterized to have identical properties as the pure OP compound 48.…”