Pharmacogenetics of Resistance to Cisplatin and Other Anticancer Drugs and the Role of Sphingolipid Metabolism

Alexander, Stephen; Swatson, William S.; Alexander, Hannah

doi:10.1007/978-1-62703-302-2_10

Cited by 6 publications

(5 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the clinical use of cisplatin is limited due to its side-effects and drug resistance (17)(18)(19). The antitumor activity of cisplatin is attributed to its ability to cause DNA damage, leading to the subsequent induction of apoptosis (20)(21)(22).…”

Section: Discussionmentioning

confidence: 99%

Ammonium chloride enhances cisplatin cytotoxicity through DNA double-strand breaks in human cervical cancer cells

Wang

Ding

et al. 2013

Oncology Reports

View full text Add to dashboard Cite

Abstract. Cisplatin (cis-diamminedichloroplatinum II, CDDP) acts as a therapeutic agent by initiating cellular apoptosis. However, side-effects and drug resistance limit the clinical use of cisplatin. Numerous studies have focused on the drug-target interactions, cellular pharmacology and pharmacokinetics of cisplatin. Newly developed treatment strategies are needed in order to be used in combination with cisplatin, with the aim to minimize toxicity and to circumvent cisplatin resistance. Ammonium chloride (NH 4 Cl) is widely used in various areas, but its use as a combination agent with cisplatin for the treatment of cancer cells has not been previously reported. In the present study, we showed that NH 4 Cl could be potentially used as an effective agent in cisplatin combination treatment of HeLa human cervical cancer (HCC) cells. Cisplatin was found to inhibit cell growth, as well as to induce cell apoptosis and DNA double-strand breaks. In addition, treatment with NH 4 Cl increased the rate of cell apoptosis and the activation of caspase-3. Particularly, we found that NH 4 Cl treatment increased cisplatin-induced phosphorylation of H 2 AX. In conclusion, our data indicate that NH 4 Cl enhances cisplatin cytotoxicity through increased DNA damage in HeLa HCC cells. IntroductionCisplatin (cis-diamminedichloroplatinum II, CDDP) is one of the most effective chemotherapeutic agents widely used for the treatment of solid tumors. However, the side-effects of cisplatin chemotherapy and resistance during the course of the treatment limit its clinical use (1-3). Cisplatin is generally considered as a cytotoxic drug which kills cancer cells by damaging DNA and inhibiting DNA synthesis. Cisplatin-induced DNA damage activates various signaling pathways to prevent or promote cell death predominantly by inducing apoptosis (4). Based on the mechanism of action of cisplatin-induced cell death, modifications to the combination methods used in chemotherapy are required to reduce the side-effects and increase the therapeutic effects of cisplatin. Autophagy inhibitors, such as 3-methyladenine and chloroquine, have been shown to effectively enhance cisplatin cytotoxity (5-8). Additional agents have been recently assessed such as bortezomib (PS-341, Velcade), a proteasome inhibitor (9,10), and histone acetyltransferase inhibitor, suberoylanilide hydroxamic acid (SAHA) (11,12). Some of these agents have been shown to confer sensitizing effects to cisplatin combination therapy.Ammonium chloride (NH 4 Cl) is an agent used for the treatment of metabolic alkalosis in clinical practice (13). NH 4 Cl was recently used as an autophagy inhibitor in in vitro studies, where it was found to affect the pH of lysosomes and to disturb the activity of autolysosomes (14-16). In the present study, we used NH 4 Cl combined with cisplatin to investigate the potentially effective use of NH 4 Cl as an agent in cisplatin combination chemotherapy.In the present study, we tested the hypothesis that the use of NH 4 Cl increases the apoptosis induced by cispl...

show abstract

Section: Discussionmentioning

confidence: 99%

Ammonium chloride enhances cisplatin cytotoxicity through DNA double-strand breaks in human cervical cancer cells

Wang

Ding

et al. 2013

Oncology Reports

View full text Add to dashboard Cite

show abstract

“…The potential of Dictyostelium cells for drug screening and pharmacogenetic studies had been illustrated in the past with studies with aminobisphosphonate, cisplatin, valproic acid and lithium (Alexander et al, 2013;Otto et al, 2016). These studies have now been extended to the characterization of curcumin and naringenin, which were found to inhibit development and/or growth (Cocorocchio et al, 2018;Swatson et al, 2017;Garige and Walters, 2015;Waheed et al, 2014).…”

Section: Dictyostelium As a Model For Biomedical Research: Recent Conmentioning

confidence: 99%

The past, present and future of Dictyostelium as a model system

Bozzaro¹

2019

Int. J. Dev. Biol.

View full text Add to dashboard Cite

The social amoeba Dictyostelium discoideum has been a preferred model organism during the last 50 years, particularly for the study of cell motility and chemotaxis, phagocytosis and macropinocytosis, intercellular adhesion, pattern formation, caspase-independent cell death and more recently autophagy and social evolution. Being a soil amoeba and professional phagocyte, thus exposed to a variety of potential pathogens, D. discoideum has also proven to be a powerful genetic and cellular model for investigating host-pathogen interactions and microbial infections. The finding that the Dictyostelium genome harbours several homologs of human genes responsible for a variety of diseases has stimulated their analysis, providing new insights into the mechanism of action of the encoded proteins and in some cases into the defect underlying the disease. Recent technological developments have covered the genetic gap between mammals and non-mammalian model organisms, challenging the modelling role of the latter. Is there a future for Dictyostelium discoideum as a model organism? Peculiarities and advantages of Dictyostelium discoideum as model organismAmong the non-mammalian model organisms, Dictyostelium discoideum (in the following Dictyostelium) is unique, due to cell division and development being totally uncoupled, and because of the transition from a unicellular to a multicellular stage during the life cycle. Growing cells proliferate by binary fission but do not differentiate, whereas starving cells undergo multicellular development and differentiation without dividing and without any need for external nutrients. Thus growth and development can be studied separately, and several non-lethal mutants can be isolated

show abstract

“…Several studies have shown the importance of targeting SphK to modulate sphingomyelin metabolsim in cancer therapy and in the treatment of several other diseases in animal models. Furthermore, the implication of sphingolipids in the development of MDR by cancer cells seems to be sufficiently proven and several reviews about this subject have been published. ,, Among these sphingolipids, the SphK and some of their receptors have presented a relation with the MDR phenomena. , These inter-relationship results are particularly relevant to SphK1. Therefore, the demonstrated role of SphKs, particularly SphK1, in the development of MDR by cancer cells makes these kinases an attractive target in developing effective therapeutics to fight against cancer.…”

Section: Summary and Perspectivesmentioning

confidence: 99%

“…Furthermore, the implication of sphingolipids in the development of MDR by cancer cells seems to be sufficiently proven and several reviews about this subject have been published. 21,27,135 Among these sphingolipids, the SphK and some of their receptors have presented a relation with the MDR phenomena. 136,137 These inter-relationship results are particularly relevant to SphK1.…”

Section: ■ Summary and Perspectivesmentioning

confidence: 99%

Importance of Sphingosine Kinase (SphK) as a Target in Developing Cancer Therapeutics and Recent Developments in the Synthesis of Novel SphK Inhibitors

2014

View full text Add to dashboard Cite

Sphingosine kinase (SphK) is an oncogenic lipid kinase that regulates the sphingolipid metabolic pathway that has been shown to play a role in numerous hyperproliferative/inflammatory diseases. The SphK isoforms (SphK1 and SphK2) catalyze the conversion of the proapoptotic substrate d-erythrosphingosine to the promitogenic/migratory product sphingosine 1-phosphate (S1P). Accumulation of S1P has been linked to the development/progression of cancer and various other diseases including, but not limited to, asthma, inflammatory bowel disease, rheumatoid arthritis, and diabetic nephropathy. SphK therefore represents a potential new target for developing novel therapeutics for cancer and other diseases. This finding has stimulated the development and evaluation of numerous SphK inhibitors over the past decade or so. In this review, we highlight the recent advancement in the field of SphK inhibitors including SphK1 and SphK2 specific inhibitors. Both sphingolipid based and nolipidic small molecule inhibitors and their importance in treatment of cancer and other diseases are discussed.

show abstract

Pharmacogenetics of Resistance to Cisplatin and Other Anticancer Drugs and the Role of Sphingolipid Metabolism

Cited by 6 publications

References 40 publications

Ammonium chloride enhances cisplatin cytotoxicity through DNA double-strand breaks in human cervical cancer cells

Ammonium chloride enhances cisplatin cytotoxicity through DNA double-strand breaks in human cervical cancer cells

The past, present and future of Dictyostelium as a model system

Importance of Sphingosine Kinase (SphK) as a Target in Developing Cancer Therapeutics and Recent Developments in the Synthesis of Novel SphK Inhibitors

Contact Info

Product

Resources

About