Click Pt(IV)-Carbohydrates Pro-Drugs for Treatment of Osteosarcoma

The selectivity vs. cancer cells has always been a major challenge for chemotherapeutic agents and in particular for cisplatin, one of the most important anticancer drugs for the treatment of several types of tumors. One strategy to overtake this challenge is to modify the coordination sphere of the metallic center with specific vectors whose receptors are overexpressed in the tumoral cell membrane, such as monosaccharides. In this paper, we report the synthesis of four novel glyco-modified Pt(IV) pro-drugs, based on cisplatin scaffold, and their biological activity against osteosarcoma (OS), a malignant tumor affecting in particular adolescents and young adults. The sugar moiety and the Pt scaffold are linked exploiting the Copper Azide Alkyne Cycloaddition (CUAAC) reaction, which has become the flagship of click chemistry due to its versatility and mild conditions. Cytotoxicity and drug uptake on three different OS cell lines as well as CSCs (Cancer Stem Cell) are described.

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NOTCH1 inhibition enhances the efficacy of conventional chemotherapeutic agents by targeting head neck cancer stem cell

Scientific Reports ◽

10.1038/srep24704 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 42

Author(s):

Zhi-Li Zhao ◽

Lu Zhang ◽

Cong-Fa Huang ◽

Si-Rui Ma ◽

Lin-Lin Bu ◽

...

Keyword(s):

Stem Cell ◽

Cancer Stem Cell ◽

Neck Cancer ◽

Chemotherapeutic Agents ◽

Head Neck Cancer ◽

Head Neck

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STEM-21. CLINICAL RELEVANCE OF CANCER STEM CELL CYTOTOXICITY ASSAY IN GUIDING TREATMENT FOR GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa215.838 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii200-ii200

Author(s):

Claudio Pier Paolo ◽

Tulika Ranjan ◽

Candace Howard ◽

Alexander Yu ◽

Linda Xu ◽

...

Keyword(s):

Stem Cell ◽

Cancer Stem Cell ◽

Clinical Investigation ◽

Therapy Resistance ◽

Chemotherapeutic Agents ◽

Cytotoxicity Assay ◽

Recurrence Time ◽

Cell Cytotoxicity ◽

Treatment Protocols ◽

Time To Recurrence

Abstract BACKGROUND. The prognosis of glioblastoma (GBM) treated with standard-of-care regimens remains very poor with a median time to recurrence of 7-9 months, and a median survival of 15-18 months. GBMs contain a small, but resilient population of cancer stem cells (CSCs) that contribute to tumor initiation, maintenance, and therapy resistance. For these reasons, its is extremely important to determine the sensitivity of CSCs to chemotherapeutic agents, with the intent of identifying more effective treatment protocols which would then translate into improved clinical survival. METHODS. We have used a novel CLIA and CAP-accredited Cancer Stem Cell Cytotoxicity Assay (ChemoID) to guide treatment for 55 Grade III and Grade IV glioma patients with the most efficacious chemotherapy treatments from a panel of FDA approved drugs or their combinations. Patients were evaluated by MRI scans and response was assessed according to RANO criteria. RESULTS: We report here a prospective clinical investigation using the ChemoID assay to measure the sensitivity and resistance of CSCs and bulk of tumor cells cultured from 55 GBM clinical specimens challenged with several chemotherapy agents, which were also correlated to the clinical response of the treated patients, independently of other biomarkers. The median recurrence time was 15 months for patients with a sensitive (>40% cell kill) CSCs test versus only 6 months for patients with a resistant CSCs test. CONCLUSIONS. The data suggests that GBM patients treated with CSC Cytotoxicity Assay-guided responsive drugs have delayed time to recurrence and the assay has the potential to help tailor chemotherapy choices to improve clinical outcomes.

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Development of APTES-Decorated HepG2 Cancer Stem Cell Membrane Chromatography for Screening Active Components fromSalvia miltiorrhiza

Analytical Chemistry ◽

10.1021/acs.analchem.6b02709 ◽

2016 ◽

Vol 88 (24) ◽

pp. 12081-12089 ◽

Cited By ~ 31

Author(s):

Xuan Ding ◽

Yan Cao ◽

Yongfang Yuan ◽

Zhirong Gong ◽

Yue Liu ◽

...

Keyword(s):

Stem Cell ◽

Cell Membrane ◽

Cancer Stem Cell ◽

Active Components ◽

Cell Membrane Chromatography ◽

Membrane Chromatography

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Pharmacological targeting of the novel β-catenin chromatin-associated kinase p38α in colorectal cancer stem cell tumorspheres and organoids

Cell Death and Disease ◽

10.1038/s41419-021-03572-4 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Martina Lepore Signorile ◽

Valentina Grossi ◽

Simone Di Franco ◽

Giovanna Forte ◽

Vittoria Disciglio ◽

...

Keyword(s):

Colorectal Cancer ◽

Stem Cell ◽

Cancer Stem Cell ◽

Kinase Inhibitor ◽

Synthetic Lethality ◽

Locally Advanced ◽

Treatment Strategies ◽

Chemotherapeutic Agents ◽

Model Systems ◽

Metastatic Dissemination

AbstractThe prognosis of locally advanced colorectal cancer (CRC) is currently unsatisfactory. This is mainly due to drug resistance, recurrence, and subsequent metastatic dissemination, which are sustained by the cancer stem cell (CSC) population. The main driver of the CSC gene expression program is Wnt signaling, and previous reports indicate that Wnt3a can activate p38 MAPK. Besides, p38 was shown to feed into the canonical Wnt/β-catenin pathway. Here we show that patient-derived locally advanced CRC stem cells (CRC-SCs) are characterized by increased expression of p38α and are “addicted” to its kinase activity. Of note, we found that stage III CRC patients with high p38α levels display reduced disease-free and progression-free survival. Extensive molecular analysis in patient-derived CRC-SC tumorspheres and APCMin/+ mice intestinal organoids revealed that p38α acts as a β-catenin chromatin-associated kinase required for the regulation of a signaling platform involved in tumor proliferation, metastatic dissemination, and chemoresistance in these CRC model systems. In particular, the p38α kinase inhibitor ralimetinib, which has already entered clinical trials, promoted sensitization of patient-derived CRC-SCs to chemotherapeutic agents commonly used for CRC treatment and showed a synthetic lethality effect when used in combination with the MEK1 inhibitor trametinib. Taken together, these results suggest that p38α may be targeted in CSCs to devise new personalized CRC treatment strategies.

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