scholarly journals Rhenium N-heterocyclic carbene complexes block growth of aggressive cancers by inhibiting FGFR- and SRC-mediated signalling

2020 ◽  
Author(s):  
Alice Domenichini ◽  
Ilaria Casari ◽  
Peter V Simpson ◽  
Nima Maheshkumar Desai ◽  
Lingfeng Chen ◽  
...  
Keyword(s):  
Side Effects ◽  
Anticancer Activity ◽  
Pancreatic Cancer Cell Line ◽  
Cancer Cell Line ◽  
Ductal Adenocarcinoma ◽  
Rhenium Complexes ◽  
Cancer Proliferation ◽  
Zebrafish Model

Abstract Background: Platinum-based anticancer drugs have been at the frontline of cancer therapy for the last 40 years, and are used in more than half of all treatments for different cancer types. However, they are not universally effective, and patients often suffer severe side effects because of their lack of cellular selectivity. There is therefore a compelling need to investigate the anticancer activity of alternative metal complexes. Here we describe the potential anticancer activity of rhenium-based complexes with preclinical efficacy in different types of solid malignancies.Methods: Kinase profile assay of rhenium complexes. Toxicology studies using zebrafish. Analysis of the growth of pancreatic cancer cell line-derived xenografts generated in zebrafish and in mice upon exposure to rhenium compounds.Results: We describe rhenium complexes which block cancer proliferation in vitro by inhibiting the signalling cascade induced by FGFR and Src. Initially, we tested the toxicity of rhenium complexes in vivo using a zebrafish model and identified one compound that displays anticancer activity with low toxicity even in the high micromolar range. Notably, the rhenium complex has anticancer activity in very aggressive cancers such as pancreatic ductal adenocarcinoma and neuroblastoma. We demonstrate the potential efficacy of this complex via a significant reduction in cancer growth in mouse xenografts.Conclusions: Our findings provide a basis for the development of rhenium-based chemotherapy agents with enhanced selectivity and limited side effects compared to standard platinum-based drugs.

scholarly journals Rhenium N-heterocyclic carbene complexes block growth of aggressive cancers by inhibiting FGFR- and SRC-mediated signalling

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Alice Domenichini ◽  
Ilaria Casari ◽  
Peter V. Simpson ◽  
Nima Maheshkumar Desai ◽  
Lingfeng Chen ◽  
...  
Keyword(s):  
Side Effects ◽  
Anticancer Activity ◽  
Pancreatic Cancer Cell Line ◽  
Cancer Cell Line ◽  
Ductal Adenocarcinoma ◽  
Rhenium Complexes ◽  
Cancer Proliferation ◽  
Zebrafish Model

Abstract Background Platinum-based anticancer drugs have been at the frontline of cancer therapy for the last 40 years, and are used in more than half of all treatments for different cancer types. However, they are not universally effective, and patients often suffer severe side effects because of their lack of cellular selectivity. There is therefore a compelling need to investigate the anticancer activity of alternative metal complexes. Here we describe the potential anticancer activity of rhenium-based complexes with preclinical efficacy in different types of solid malignancies. Methods Kinase profile assay of rhenium complexes. Toxicology studies using zebrafish. Analysis of the growth of pancreatic cancer cell line-derived xenografts generated in zebrafish and in mice upon exposure to rhenium compounds. Results We describe rhenium complexes which block cancer proliferation in vitro by inhibiting the signalling cascade induced by FGFR and Src. Initially, we tested the toxicity of rhenium complexes in vivo using a zebrafish model and identified one compound that displays anticancer activity with low toxicity even in the high micromolar range. Notably, the rhenium complex has anticancer activity in very aggressive cancers such as pancreatic ductal adenocarcinoma and neuroblastoma. We demonstrate the potential efficacy of this complex via a significant reduction in cancer growth in mouse xenografts. Conclusions Our findings provide a basis for the development of rhenium-based chemotherapy agents with enhanced selectivity and limited side effects compared to standard platinum-based drugs.

scholarly journals Rhenium N-heterocyclic Carbene Complexes Block Growth of Aggressive Cancers by Inhibiting FGFR- and SRC-Mediated Signalling

2020 ◽  
Author(s):  
Alice Domenichini ◽  
Ilaria Casari ◽  
Peter V Simpson ◽  
Nima Maheshkumar Desai ◽  
Lingfeng Chen ◽  
...  
Keyword(s):  
Side Effects ◽  
Anticancer Activity ◽  
Pancreatic Cancer Cell Line ◽  
Cancer Cell Line ◽  
Ductal Adenocarcinoma ◽  
Rhenium Complexes ◽  
Cancer Proliferation ◽  
Zebrafish Model

Abstract Background: Platinum-based anticancer drugs have been at the frontline of cancer therapy for the last 40 years, and are used in more than half of all treatments for different cancer types. However, they are not universally effective, and patients often suffer severe side effects because of their lack of cellular selectivity. There is therefore a compelling need to investigate the anticancer activity of alternative metal complexes. Here we describe the potential anticancer activity of rhenium-based complexes with preclinical efficacy in different types of solid malignancies.Methods: Kinase profile assay of rhenium complexes. Toxicology studies using zebrafish. Analysis of the growth of pancreatic cancer cell line-derived xenografts generated in zebrafish and in mice upon exposure to rhenium compounds.Results: We describe rhenium complexes which block cancer proliferation in vitro by inhibiting the signalling cascade induced by FGFR and Src. Initially, we tested the toxicity of rhenium complexes in vivo using a zebrafish model and identified one compound that displays anticancer activity with low toxicity even in the high micromolar range. Notably, the rhenium complex has anticancer activity in very aggressive cancers such as pancreatic ductal adenocarcinoma and neuroblastoma. We demonstrate the potential efficacy of this complex via a significant reduction in cancer growth in mouse xenografts.Conclusions: Our findings provide a basis for the development of rhenium-based chemotherapy agents with enhanced selectivity and limited side effects compared to standard platinum-based drugs.

scholarly journals Cyathus striatus Extract Induces Apoptosis in Human Pancreatic Cancer Cells and Inhibits Xenograft Tumor Growth In Vivo

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2017
Author(s):  
Lital Sharvit ◽  
Rinat Bar-Shalom ◽  
Naiel Azzam ◽  
Yaniv Yechiel ◽  
Solomon Wasser ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Pancreatic Cancer Cell Line ◽  
Cancer Cell Line ◽  
Culture Liquid ◽  
Human Pancreatic Cancer ◽  
P53 Signaling ◽  
Pancreatic Cancer Cells

Pancreatic cancer is a highly lethal disease with limited options for effective therapy and the lowest survival rate of all cancer forms. Therefore, a new, effective strategy for cancer treatment is in need. Previously, we found that a culture liquid extract of Cyathus striatus (CS) has a potent antitumor activity. In the present study, we aimed to investigate the effects of Cyathus striatus extract (CSE) on the growth of pancreatic cancer cells, both in vitro and in vivo. The proliferation assay (XTT), cell cycle analysis, Annexin/PI staining and TUNEL assay confirmed the inhibition of cell growth and induction of apoptosis by CSE. A Western blot analysis demonstrated the involvement of both the extrinsic and intrinsic apoptosis pathways. In addition, a RNAseq analysis revealed the involvement of the MAPK and P53 signaling pathways and pointed toward endoplasmic reticulum stress induced apoptosis. The anticancer activity of the CSE was also demonstrated in mice harboring pancreatic cancer cell line-derived tumor xenografts when CSE was given for 5 weeks by weekly IV injections. Our findings suggest that CSE could potentially be useful as a new strategy for treating pancreatic cancer.

scholarly journals Potentially Curative Therapeutic Activity of NEO212, a Perillyl Alcohol-Temozolomide Conjugate, in Preclinical Cytarabine-Resistant Models of Acute Myeloid Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3385
Author(s):  
Axel H. Schönthal ◽  
Steve Swenson ◽  
Radu O. Minea ◽  
Hye Na Kim ◽  
Heeyeon Cho ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Side Effects ◽  
Anticancer Activity ◽  
Myeloid Leukemia ◽  
Perillyl Alcohol ◽  
Therapeutic Activity ◽  
Acute Myeloid

Despite progress in the treatment of acute myeloid leukemia (AML), the clinical outcome remains suboptimal and many patients are still dying from this disease. First-line treatment consists of chemotherapy, which typically includes cytarabine (AraC), either alone or in combination with anthracyclines, but drug resistance can develop and significantly worsen prognosis. Better treatments are needed. We are developing a novel anticancer compound, NEO212, that was created by covalent conjugation of two different molecules with already established anticancer activity, the alkylating agent temozolomide (TMZ) and the natural monoterpene perillyl alcohol (POH). We investigated the anticancer activity of NEO212 in several in vitro and in vivo models of AML. Human HL60 and U937 AML cell lines, as well as different AraC-resistant AML cell lines, were treated with NEO212 and effects on cell proliferation, cell cycle, and cell death were investigated. Mice with implanted AraC-sensitive or AraC-resistant AML cells were dosed with oral NEO212, and animal survival was monitored. Our in vitro experiments show that treatment of cells with NEO212 results in growth inhibition via potent G2 arrest, which is followed by apoptotic cell death. Intriguingly, NEO212 was equally potent in highly AraC-resistant cells. In vivo, NEO212 treatment strikingly extended survival of AML mice and the majority of treated mice continued to thrive and survive without any signs of illness. At the same time, we were unable to detect toxic side effects of NEO212 treatment. All in all, the absence of side effects, combined with striking therapeutic activity even in an AraC-resistant context, suggests that NEO212 should be developed further toward clinical testing.

Ensituximab (E) in patients (pts) with refractory metastatic colorectal cancer (mCRC): Results of a phase I/II clinical trial.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3081-3081 ◽  
Author(s):  
Richard D. Kim ◽  
Philip M. Arlen ◽  
Kwong Y. Tsang ◽  
Sharon Mavroukakis ◽  
Anjum Zaki ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Trial ◽  
Phase 1 ◽  
Pancreatic Cancer Cell Line ◽  
Cancer Cell Line ◽  
Serum Cytokine ◽  
Open Label ◽  
Related Factors

3081 Background: E is an investigational, novel, chimeric monoclonal IgG1 antibody derived from an immunogenic neoantigen with sequence homology to MUC5AC that is preferentially expressed with exquisite specificity to pancreatic cancer and CRC. Its mechanism of action is via antibody-dependent cellular cytotoxicity (ADCC). The efficacy and safety of E was evaluated in a single-arm, open-label, phase 1/2 clinical trial of adult pts with refractory mCRC. Methods: Pts were selected based on > 20% expression of tumor antigen, as measured by immunohistochemistry. Based on phase 1 results, E was administered 3 mg/kg IV every 2 weeks until unacceptable toxicity or disease progression. Primary endpoint was overall survival (OS). Serum cytokine levels were analyzed at baseline, day 4, and day 15. E-mediated ADCC of CD16 genotype V/V, V/F, and F/F pt PBMCs was measured with an IN-111 release assay using the E target-expressing ASPC-1 pancreatic cancer cell line. Results: Fifty-seven and 63 pts were evaluable for OS and safety, respectively. Median OS was significantly longer than historical control: 6.8 vs 5.0 months (mo); p = 0.007; 95% CI: 5.39,8.02. Three pts were alive at end of study (21, 21, and 24 mo); 21 pts survived ≥ 12 mo. Pts had a median of 4 prior therapies (range 2-9); 25% had received regorafenib. Forty-seven pts were evaluable by RECIST, and 20 (43%) had stable disease of target lesions at end of first course (day 57). E was well tolerated, with < 2% grade 3 and no grade 4 toxicities. There were no trends in serum cytokine and chemokine levels. Analysis of 56 samples (8 V/V, 26 V/F, 17 F/F, and 5 undetermined) showed that V/V PBMCs had significantly higher E-mediated ADCC than PBMCs harboring other genotypes. No correlation between CD16 polymorphism and pt outcome was observed. Conclusions: E demonstrated excellent tolerability and encouraging OS in this heavily pretreated population. Correlative in vitro data suggest that E can mediate higher levels of ADCC activity in individuals with a V/V versus other genotypes. The lack of correlation between CD16 polymorphism and pt outcomes in this study suggests that other immune-related factors (under investigation) may impact the efficacy of E in vivo. Clinical trial information: NCT01040000.

scholarly journals Attenuation of Pancreatic Cancer In Vitro and In Vivo via Modulation of Nrf2 and NF-κB Signaling Pathways by Natural Compounds

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3556
Author(s):  
Marta Cykowiak ◽  
Robert Kleszcz ◽  
Małgorzata Kucińska ◽  
Jarosław Paluszczak ◽  
Hanna Szaefer ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Signaling Pathways ◽  
Cell Line ◽  
Target Genes ◽  
Pancreatic Cancer Cell Line ◽  
Cancer Cell Line ◽  
In Vivo Studies ◽  
Phenethyl Isothiocyanate

Pancreatic cancer is a disease in which deregulation of signaling pathways plays a key role, thus searching for their novel modulators is a promising therapeutic strategy. Hence, in this study, the effect of phytochemical combinations on the canonical and non-canonical activation of Nrf2 and its interaction with the NF-κB pathway was evaluated in extensively proliferating pancreatic cancer cell line, PSN-1, in comparison to non-cancerous MS1 cells. The activation of Nrf2 and NF-κB, expression of their target genes, and effect on cell survival were assessed in PSN-1 cells. The tumor burden was evaluated in mice carrying xenografts. PSN-1 cells were more sensitive to the tested compounds as compared to the MS1 cell line. Combination of xanthohumol and phenethyl isothiocyanate was more effective than single compounds at decreasing the canonical and non-canonical activation of Nrf2 in PSN-1 cancer cells. Decreased activation of NF-κB, and subsequent reduced cytosolic COX-2 and nuclear STAT3 level indicated their anti-inflammatory and pro-apoptotic activities. In vivo studies showed the partial response in groups treated with xanthohumol or the combination of xanthohumol and phenethyl isothiocyanate. Overall, these results suggest that the combination of xanthohumol and phenethyl isothiocyanate may be a promising therapeutic candidate against pancreatic cancer.

scholarly journals CCL28 Downregulation Attenuates Pancreatic Cancer Progression Through Tumor Cell-Intrinsic and -Extrinsic Mechanisms

2021 ◽  
Vol 20 ◽  
pp. 153303382110689
Author(s):  
Jingjing Yan ◽  
Pengkun Yuan ◽  
Liming Gui ◽  
Zhixue Wang ◽  
Pan Yin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Cell ◽  
Cancer Progression ◽  
Pancreatic Cancer Cell Line ◽  
Cancer Cell Line ◽  
Suppressor Cells ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Syngeneic Mouse Model

C-C motif chemokine ligand 28 (CCL28) has been reported to be pro-tumoral in several cancer types. However, the role of CCL28 in pancreatic ductal adenocarcinoma (PDAC) progression remains unclear. CCL28 mRNA expression in tumors from PDAC patients was found to be elevated as compared to normal pancreas. CCL28 expression was also negatively correlated with overall survival (OS) in pancreatic cancer patients. Our in vitro experiments showed that CCL28 knockdown impairs the proliferation of mouse pancreatic cancer cell line PAN02. Moreover, in both immunocompetent syngeneic mice and immunodeficient NOD-SCID mice, CCL28 deficiency significantly attenuated the growth of subcutaneous PAN02 tumors. In syngeneic mouse model, CCL28 downregulation remodeled the pancreatic tumor microenvironment by suppressing the infiltration of both regulatory T (Treg) cells, myeloid-derived suppressor cells, and activated pancreatic stellate cells, and upregulating the expression of lymphocyte cytotoxic proteins including perforin and granzyme B. In conclusion, our work demonstrates that CCL28 is a potential target for pancreatic cancer treatment and CCL28 blockade could inhibit tumor growth through both tumor-cell-intrinsic and extrinsic mechanisms.

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