Synthesis, Biological Evaluation and Low-Toxic Formulation Development of Glycosylated Paclitaxel Prodrugs

Paclitaxel (PTX) is a famous anti-cancer drug with poor aqueous solubility. In clinical practices, Cremophor EL (polyethoxylated castor oil), a toxic surfactant, is used for dissolution of PTX, which accounts for serious side effects. In the present study, a single glucose-conjugated PTX prodrug (SG-PTX) and a double glucose-conjugated PTX prodrug (DG-PTX) were synthesized with a glycosylated strategy via succinate linkers. Both of the two prodrugs presented significant solubility improvement and drug-like lipophilicities. Compared to DG-PTX, SG-PTX manifested more promising release of the parent drug in serum. A high percentage of PTX released from SG-PTX could be detected after enzymatic hydrolysis of β-glucuronidase. Besides, both of the two prodrugs exhibited effective cytotoxicity against breast cancer cells and ovarian cancer cells, but presented reduced cytotoxicity against normal breast cells. Moreover, SG-PTX manifested impressive solubility in a low toxic formulation (without ethanol) with a different percentage of Cremophor EL. These results indicated that glycosylation is a promising strategy for PTX modification and SG-PTX may be a feasible and potential type of PTX prodrug. In addition, ethanol-free formulation with a low percentage of Cremophor EL might have the potential to develop a safer formulation for further studies of glycosylated PTX prodrugs.

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Searching for a New Anti‐Cancer Drug: Investigation of KY Hemp‐Induced Apoptosis in Ovarian Cancer Cells

The FASEB Journal ◽

10.1096/fasebj.2018.32.1_supplement.616.1 ◽

2018 ◽

Vol 32 (S1) ◽

Author(s):

Wasana K. Sumanasekera ◽

Christina Johnson ◽

Anh‐Thoa Pham ◽

Brijesh Patel ◽

Anjali Sivamohan ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Cancer Drug ◽

Ovarian Cancer Cells ◽

Drug Investigation ◽

Anti Cancer ◽

Induced Apoptosis

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Differences in cisplatin distribution in sensitive and resistant ovarian cancer cells: a TEM/NanoSIMS study

Metallomics ◽

10.1039/c7mt00153c ◽

2017 ◽

Vol 9 (10) ◽

pp. 1413-1420 ◽

Cited By ~ 18

Author(s):

Ronald F. S. Lee ◽

Tina Riedel ◽

Stéphane Escrig ◽

Catherine Maclachlan ◽

Graham W. Knott ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Acquired Resistance ◽

Cancer Drug ◽

Ovarian Cancer Cells ◽

Anti Cancer

Cisplatin is a widely used anti-cancer drug, but its effect is often limited by acquired resistance to the compound during treatment.

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Synergistic effects of type I PRMT and PARP inhibitors against non-small cell lung cancer cells

Clinical Epigenetics ◽

10.1186/s13148-021-01037-1 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Claudia Dominici ◽

Nicolas Sgarioto ◽

Zhenbao Yu ◽

Laura Sesma-Sanz ◽

Jean-Yves Masson ◽

...

Keyword(s):

Combination Therapy ◽

Cancer Cells ◽

Parp Inhibitors ◽

Small Cell ◽

Synergistic Interaction ◽

Cancer Drug ◽

Ovarian Cancer Cells ◽

Type I ◽

Small Cell Lung ◽

Cell Lung Carcinoma

Abstract Background Non-small cell lung carcinoma (NSCLC) is a leading cause of cancer-related death and represents a major health burden worldwide. Current therapies for NSCLC include chemotherapy, immunotherapy, and targeted molecular agents such as tyrosine kinase inhibitors and epigenetic drugs such as DNA methyltransferase inhibitors. However, survival rates remain low for patients with NSCLC, especially those with metastatic disease. A major cause for therapeutic failure is drug resistance, highlighting the need for novel therapies and combination strategies. Given that epigenetic modulators such as protein arginine methyltransferases (PRMTs) are frequently overexpressed in cancers, PRMT inhibitors are a promising class of cancer therapeutics. We screened a library of epigenetic and anticancer drugs to identify compounds that would synergize with MS023, a type I PRMT inhibitor, in decreasing the viability of methylthioadenosine phosphorylase (MTAP)-negative NSCLC cells. Results Among 181 compounds, we identified PARP inhibitors (PARPi) as having a strong synergistic interaction with type I PRMT inhibition. The combination of MS023 and the PARP inhibitor BMN-673 (Talazoparib) demonstrated strong synergistic interaction at low nanomolar concentrations in MTAP-negative NSCLC cell lines A549, SK-LU-1 and HCC4006. The re-introduction of MTAP decreased the sensitivity of the combination therapy in A549. The combination therapy resulted in elevated γ-H2AX foci indicating increased DNA damage causing decreased cell viability. Lastly, the combination therapy was effective in PARPi resistant ovarian cancer cells, suggesting that type I PRMT inhibitors could mitigate PARPi resistance, thus potentially having an important clinical impact for cancer treatment. Conclusions These findings identify a novel cancer drug combination therapy, which is more potent than the separate single-agent therapies. Thus, combining PARP inhibitors and type I PRMT inhibitors represents a new therapeutic opportunity for MTAP-negative NSCLC and certain cancer cells resistant to PARP inhibitors.

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Selenite-induced ROS/AMPK/FoxO3a/GABARAPL-1 signaling pathway modulates autophagy that antagonize apoptosis in colorectal cancer cells

Discover Oncology ◽

10.1007/s12672-021-00427-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Hailing Yu ◽

Yin Huang ◽

Yanming Ge ◽

Xiaopeng Hong ◽

Xi Lin ◽

...

Keyword(s):

Colorectal Cancer ◽

Western Blot ◽

Cancer Cells ◽

Stress Responses ◽

Sodium Selenite ◽

Xenograft Model ◽

Cancer Drug ◽

Clinical Practices ◽

Colorectal Cancer Cells

AbstractPrevious studies have shown that selenium possessed chemotherapeutic effect against multiple malignant cancers, inducing diverse stress responses including apoptosis and autophagy. Selenite was previously shown to induce apoptosis and autophagy in colorectal cancer cells. However, the relationship between selenite-induced apoptosis and autophagy was not fully understood. Our results revealed a pro-survival role of selenite-induced autophagy against apoptosis in colorectal cancer cells. Real-time PCR array of autophagy-related genes showed that GABARAPL-1 was significantly upregulated in colorectal cancer cells, which was confirmed by western blot and immunofluorescence results. Knockdown of GABARAPL-1 significantly inhibited selenite-induced autophagy and enhanced apoptosis. Furthermore, we found that selenite-induced upregulation of GABARAPL-1 was caused by upregulated p-AMPK and FoxO3a level. Their interaction was correlated with involved in regulation of GABARAPL-1. We observed that activation and inhibition of AMPK influenced both autophagy and apoptosis level via FoxO3a/ GABARAPL-1 signaling, implying the pro-survival role of autophagy against apoptosis. Importantly, we corroborated these findings in a colorectal cancer xenograft animal model with immunohistochemistry and western blot results. Collectively, these results show that sodium selenite could induce ROS/AMPK/FoxO3a/GABARAPL-1-mediated autophagy and downregulate apoptosis in both colorectal cancer cells and colon xenograft model. These findings help to explore sodium selenite as a potential anti-cancer drug in clinical practices.

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