Taxanes (paclitaxel and docetaxel) are one of the most useful classes of anticancer drugs. Taxanes are highly hydrophobic; therefore, these drugs must be dissolved in organic solvents (polysorbate or Cremophor EL), which contribute to their toxicities. To reduce this toxicity and to enhance their efficacy, novel formulations have been developed. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is an albumin-stabilized, Cremophor-free, and water-soluble nanoparticle formulation of paclitaxel. Nab-paclitaxel has better solubility and less infusion-associated toxicity compared to solvent-based paclitaxel. Additionally, nab-paclitaxel can be given at higher doses and concentrations compared with solvent-based paclitaxel. Based on its superior clinical efficacy and safety profile, nab-paclitaxel received FDA approval for metastatic breast cancer (2008) and NSCLC (2011). Among gastrointestinal cancers, it is now approved in the USA for treating patients with metastatic adenocarcinoma of the pancreas as first-line therapy in combination with gemcitabine. Furthermore, several clinical trials have suggested the potential efficacy of nab-paclitaxel as a single agent or in combination with other agents for the treatment of metastatic esophageal, gastric, bowel, and biliary tract cancers. Nab-paclitaxel has been demonstrated to have greater overall response rates (ORR) with enhanced progression-free survival (PFS), overall survival (OS) and a superior safety profile with fewer adverse effects in patients with gastrointestinal tract cancers. This review summarizes the advantages associated with nab-paclitaxel-based regimens in terms of improving clinical efficacy and the safety profile in upper gastrointestinal cancer.
Introduction: Esophageal adenocarcinoma (EAC) is one of the most aggressive human cancers with poor prognosis, and the overall 5-year survival rate is less than 20 percent. Prognosis for EAC remains poor even with modern combination therapies due to high resistance to chemotherapy. Therefore, new therapeutic approaches for EAC treatment improvements are urgently needed. Hypoxia or insufficient tissue oxygenation contributes to cancer aggressiveness and poor clinical prognosis. Overexpression of hypoxia-inducible factor 1-alpha (HIF-1 alpha) and immunosuppressive CD73, an ecto-5’-nucleotidase enzyme in cancer can give rise to tumor progression with drug resistance. CD73 has never been proposed as a therapeutic target in EAC and its relationship with hypoxia or HIF-1 alpha has not also been investigated in EAC. In this study, we therefore investigated the therapeutic targeting of HIF-1 alpha and CD73 by acriflavine in experimental EAC. Methods: Hypoxia in EAC cells were induced by 3D culture and hypoxic exposure. NanoCulture® plates and dishes were used for 3D cultures. For hypoxic exposure, cells were placed in a sealed modular incubator chamber flushed with a gas mixture containing 1% O2, 5% CO2 and 94% N2. Hypoxic status was detected by adding hypoxia probe LOX-1 and fluorescent microscopy. Nanoparticle albumin-bound paclitaxel (NPT) was used as chemotherapeutic agent, whereas acriflavine was used as hypoxia-targeting agent. In vitro cell growth was detected by WST-1 and Cell Titer-Glo (CTG) luminescent assays, in vivo tumor growth was detected by measuring subcutaneous xenografts, apoptosis was detected by cleaved caspase 3/PARP expressions and hypoxia-targeting was detected by HIF-1 alpha/CD73 expressions. Results: We observed overexpression of both HIF-1 alpha and CD73 in 3D culture and hypoxic exposure of EAC cells. Interestingly acriflavine treatment drastically inhibited both HIF-1 alpha and CD73 expression in EAC 3D culture and hypoxic exposure. 3D culture was more resistant to antiproliferative effect of chemotherapeutic agent NPT over 2D monolayer culture. Contrary to that, hypoxia-targeting agent acriflavine showed stronger antiproliferative effects in 3D culture than in 2D culture. We also observed hypoxia inside the 3D culture spheroids. In addition, acriflavine showed significant in vivo antitumor efficacy both as monotherapy and in combination with NPT. In subcutaneous xenografts using OE19 EAC cells, acriflavine monotherapy exhibited a significant decrease in relative tumor volume to 55.02% compared to control (p=0.04) and addition of NPT with acriflavine also showed a significant enhancement effect of tumor regression as tumor size decreased to 32.70% compared to control (p=0.002). Conclusion: These results support the potential of acriflavine as HIF-1 alpha and CD73 targeting and its combination with chemotherapy NPT as an effective option for EAC therapy. Citation Format: Md Sazzad Hassan, Aktar Ali, Saisantosh Ponna, Dimitri Scofield, Niranjan Awasthi, Mark Jantz, Urs von Holzen. Therapeutic targeting of HIF-1 alpha induced CD73 expression in experimental esophageal adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3960.
Introduction: Esophageal adenocarcinoma (EAC) is an aggressive form of cancer with 5-year survival rates under 20%. The low survival rate is due largely to advanced stage upon diagnosis. Improved treatment options remain essential in combating the disease and bolstering patient outcomes. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a chemotherapeutic receiving attention for its potential in EAC treatment. The taxane has exhibited greater specificity for targeting cancer cells while decreasing cytotoxic effects to adjacent healthy populations. Unfortunately, chemoresistance remains an issue surrounding adequate treatment regimes. Epinephrine and its receptor, β2 adrenergic, have been shown to dysregulate various oncogenic pathways and reduce chemotherapeutics efficacy. Typically associated with pain management and addiction treatment, Methadone hydrochloride has been investigated for its potential to block the oncogenic effects of epinephrine and strengthen the impact of chemotherapeutics. In this study, we evaluated the enhancement of apoptosis by combination of nab-paclitaxel and methadone, and we demonstrated the ability of methadone to block epinephrine-induced chemoresistance. Method: We utilized PCR to elucidate EAC cell lines with the greatest expression of Mu opioid and β2 adrenergic receptors. Next, we investigated adequate dosages of methadone and epinephrine for the EAC cell lines by WST-1 assay. WST-1 assays were also utilized to determine cell growth under co-administration of nab-paclitaxel and methadone as well as methadone and epinephrine. Propidium iodine cell viability flow cytometry assay was used to detect cell death. Annexin V staining was utilized to further distinguish between apoptotic and necroptotic cells. Result: OE19 and OE33 cell lines showed increased expression of Mu and β2 adrenergic receptors, ensuring the cells were capable of binding to methadone or epinephrine. WST-1 assays established 100 nM of epinephrine and 200 nM of methadone as optimal dosages for both cell lines. Our previous studies demonstrated that about 5.85 uM of nab-paclitaxel (5ug/mL) induces apoptosis in OE19 and OE33. Propidium iodide staining showed the enhancement of cell death under combination treatment of nab-paclitaxel and methadone. Annexin V staining confirmed that the effect was via apoptosis. Conclusion: The current study demonstrated methadone’s ability to block epinephrine-induced cell proliferation and showed an enhanced effect on apoptosis when combining nab-paclitaxel with methadone in EAC treatment. Citation Format: Nicholas Cwidak, Sazzad Hassan, Chloe Johnson, Saisantosh Ponna, Niranjan Awasthi, Urs von Holzen. Methadone hydrochloride blocks epinephrine-induced proliferation and enhances apoptotic effects of nab-paclitaxel in esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2624.
Introduction: Esophageal adenocarcinoma (EAC) is one of the fastest growing cancers in the Western world and the overall 5-year survival rate of EAC is below 20 percent. Epidemiological studies have linked obesity with EAC. Insulin-like growth factor (IGF) signaling is an important mediator in obesity-associated EAC. Paclitaxel (PT) has been used in combination with carboplatin as a standard combination therapy for advanced EAC. PT required emulsification with solvents which have resulted in serious adverse effects in patients. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is an albumin-stabilized, cremophor-free and water-soluble nanoparticle formulation of PT. Nab-paclitaxel has recently shown greater efficacy over PT in EAC. In this study, we evaluated the potential of targeting IGF signaling and improvement in nab-paclitaxel response by the addition of BMS-754807 in experimental EAC. Methods: We first evaluated the phosphorylation status of IGF-1R/IR protein by Western blot in a panel of EAC cell lines. BMS-754807 and nab-paclitaxel, alone or in combination were tested for effects on cell growth, cell apoptosis, cell migration and cell cycle analyses of EAC cell lines detected respectively by WST-1 assay, Western blotting, would healing scratch assay and propidium iodide flow cytometry. We then explored the antitumor efficacy of BMS-754807 and nab-paclitaxel monotherapy and in combination in murine subcutaneous xenograft and peritoneal metastatic survival models of human EAC. Results: BMS-754807 dose-dependently inhibited in-vitro cell proliferation of EAC cell lines having phosphorylation of IGF-1R/IR protein. The co-administration of BMS-754807 and nab-paclitaxel effectively enhanced cell growth inhibition, cleavage of caspase-3 and PARP, in-vitro wound healing inhibition and cell cycle arrest at sub G0/G1 phase. BMS-754807 in combination with nab-paclitaxel treatment resulted in significantly higher antitumor efficacy by increasing intratumoral apoptosis and survival benefit compared with BMS-754807 or nab-paclitaxel treatment alone. In subcutaneous xenografts using OE19 cells, average net tumor growth after two weeks in different therapy groups was 558.67 mm3 in control, 208.47 mm3 after BMS-754807 (p=0.043), 104.60 mm3 after nab-paclitaxel (p=0.013), and 14.30 mm3 after BMS-754807 plus nab-paclitaxel (p=0.0005). There was a significant increase in median animal survival after BMS-754807 plus nab-paclitaxel treatment (85 days) compared to control (47 days, p=0.0034), BMS-754807 monotherapy (57 days, p=0.0021) or nab-paclitaxel (68 days, p=0.0339) monotherapy. Conclusion: These results support the potential of BMS-754807 in combination with nab-paclitaxel as an effective option for EAC therapy. Citation Format: Md Sazzad Hassan, Nicholas Cwidak, Chloe Johnson, Saisantosh Ponna, Niranjan Awasthi, Urs von Holzen. BMS-754807, a small-molecule inhibitor of insulin-like growth factor-1 receptor/insulin receptor is cytotoxic to esophageal adenocarcinoma cells and enhances nab-paclitaxel response in experimental esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1066.
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