Histamine H1 receptor antagonists selectively kill cisplatin-resistant human cancer cells

AbstractCancer therapy is often hampered by the disease’s development of resistance to anticancer drugs. We previously showed that the autonomously upregulated product of fibroblast growth factor 13 gene (FGF13; also known as FGF homologous factor 2 (FHF2)) is responsible for the cisplatin resistance of HeLa cisR cells and that it is likely responsible for the poor prognosis of cervical cancer patients treated with cisplatin. Here we show that cloperastine and two other histamine H1 receptor antagonists selectively kill HeLa cisR cells at concentrations that little affect parental HeLa S cells. The sensitivity of HeLa cisR cells to cloperastine was abolished by knocking down FGF13 expression. Cisplatin-resistant A549 cisR cells were similarly susceptible to cloperastine. H2, H3, and H4 receptor antagonists showed less or no cytotoxicity toward HeLa cisR or A549 cisR cells. These results indicate that histamine H1 receptor antagonists selectively kill cisplatin-resistant human cancer cells and suggest that this effect is exerted through a molecular mechanism involving autocrine histamine activity and high-level expression of FGF13. We think this represents a potential opportunity to utilize H1 receptor antagonists in combination with anticancer agents to treat cancers in which emergent drug-resistance is preventing effective treatment.

Download Full-text

Syntheses of l-Rhamnose-Linked Amino Glycerolipids and Their Cytotoxic Activities against Human Cancer Cells

Molecules ◽

10.3390/molecules25030566 ◽

2020 ◽

Vol 25 (3) ◽

pp. 566

Author(s):

Makanjuola Ogunsina ◽

Pranati Samadder ◽

Temilolu Idowu ◽

Mark Nachtigal ◽

Frank Schweizer ◽

...

Keyword(s):

Cancer Cells ◽

Anticancer Agents ◽

Human Cancer ◽

Cytotoxic Activities ◽

Drug Resistant ◽

Ether Lipids ◽

Human Cancer Cell Lines ◽

Human Cancer Cells ◽

Synthetic Procedure ◽

Major Impediment

A major impediment to successful cancer treatment is the inability of clinically available drugs to kill drug-resistant cancer cells. We recently identified metabolically stable l-glucosamine-based glycosylated antitumor ether lipids (GAELs) that were cytotoxic to chemotherapy-resistant cancer cells. In the absence of commercially available l-glucosamine, many steps were needed to synthesize the compound and the overall yield was poor. To overcome this limitation, a facile synthetic procedure using commercially available l-sugars including l-rhamnose and l-glucose were developed and the l-GAELs tested for anticancer activity. The most potent analog synthesized, 3-amino-1-O-hexadecyloxy-2R-(O–α-l-rhamnopyranosyl)-sn- glycerol 3, demonstrated a potent antitumor effect against human cancer cell lines derived from breast, prostate, and pancreas. The activity observed was superior to that observed with clinical anticancer agents including cisplatin and chlorambucil. Moreover, like other GAELs, 3 induced cell death by a non-membranolytic caspase-independent pathway.

Download Full-text

Inhibitors of aldehyde dehydrogenases of the 1A subfamily as putative anticancer agents: Kinetic characterization and effect on human cancer cells

Chemico-Biological Interactions ◽

10.1016/j.cbi.2019.04.004 ◽

2019 ◽

Vol 306 ◽

pp. 123-130 ◽

Cited By ~ 3

Author(s):

Rafael Jiménez ◽

Raquel Pequerul ◽

Adrián Amor ◽

Julia Lorenzo ◽

Kamel Metwally ◽

...

Keyword(s):

Cancer Cells ◽

Anticancer Agents ◽

Human Cancer ◽

Kinetic Characterization ◽

Aldehyde Dehydrogenases ◽

Human Cancer Cells

Download Full-text

Synthesis of New Hydrazone Derivatives and Evaluation of their Efficacy as Proliferation Inhibitors in Human Cancer Cells

Medicinal Chemistry ◽

10.2174/1573406415666190128100524 ◽

2019 ◽

Vol 15 (8) ◽

pp. 903-910 ◽

Cited By ~ 1

Author(s):

Piotr Świątek ◽

Jolanta Saczko ◽

Nina Rembiałkowska ◽

Julita Kulbacka

Keyword(s):

Cancer Cells ◽

Anticancer Agents ◽

Human Cancer ◽

Anticancer Activities ◽

Human Cancer Cells ◽

Viability Assay ◽

Resistant Phenotype ◽

Potent Inhibition ◽

Drug Resistant Phenotype ◽

Mcf 7

Background: Hydrazine-hydrazones represent a group of bioactive compounds that display antibacterial, anti-inflammatory, antiviral or anticancer activities. Methods: The group of new derivatives was evaluated by the viability assay in human cancer and normal cells. Results: The dimethylpyridine hydrazones showed potent inhibition of cell proliferation of breast, colon cancer cells, human melanoma and glioblastoma. Compound 12 inhibited proliferation of cancer cells exhibiting a drug-resistant phenotype (MCF-7/DX and LoVoDX) at low millimolar concentrations. Whereas, antimelanoma activity was revealed by Compounds 2, 4, 7 and 12. Conclusion: The present results highlighted newly synthetized hydrazine derivatives an excellent base for the design of new anticancer agents and resistance inhibitors.

Download Full-text

Micelle-in-Liposomes for Sustained Delivery of Anticancer Agents That Promote Potent TRAIL-Induced Cancer Cell Apoptosis

Molecules ◽

10.3390/molecules26010157 ◽

2020 ◽

Vol 26 (1) ◽

pp. 157

Author(s):

Zhenjiang Zhang ◽

Sagar B. Patel ◽

Michael R. King

Keyword(s):

Cancer Cells ◽

Cancer Cell ◽

Anticancer Agents ◽

Water Solubility ◽

Human Cancer ◽

Human Cancer Cells ◽

Cancer Cell Death ◽

Apoptotic Effect ◽

New Formulation ◽

Aqueous Core

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces cancer cell-specific apoptosis and has garnered intense interest as a promising agent for cancer treatment. However, the development of TRAIL has been hampered in part because most human cancer cells are resistant to TRAIL. A few small molecules including natural compounds such as piperlongumine (PL) have been reported to sensitize cancer cells to TRAIL. We prepared a novel type of nanomaterial, micelle-in-liposomes (MILs) for solubilization and delivery of PL. PL-loaded MILs were used to sensitize cancer cells to TRAIL. As visualized by cryo-TEM, micelles were successfully loaded inside the aqueous core of liposomes. The MILs increased the water solubility of PL by ~20 fold. A sustained PL release from MILs in physiologically relevant buffer over 7 days was achieved, indicating that the liposomes prevented premature drug release from the micelles in the MILs. Also demonstrated is a potent synergistic apoptotic effect in cancer cells by PL MILs in conjunction with liposomal TRAIL. MILs provide a new formulation and delivery vehicle for hydrophobic anticancer agents, which can be used alone or in combination with TRAIL to promote cancer cell death.

Download Full-text