Nature of the charged head group dictates the anticancer potential of lithocholic acid-tamoxifen conjugates for breast cancer therapy

Yadav, Kavita; Bhargava, Priyanshu; Bansal, Sandhya; Singh, Manish; Gupta, Shweta; Sandhu, Geeta; Kumar, Sandeep; Sreekanth, Vedagopuram; Bajaj, Avinash

doi:10.1039/c4md00289j

Cited by 13 publications

(16 citation statements)

References 41 publications

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“…23 In addition, the presence of a free hydroxyl and a carboxyl group makes it a suitable lipid carrier for tethering of drugs, and head groups. 25 Phosphocholine, providing an amphiphilic character to lipids, is the most compatible headgroup due to its abundance in cell membranes. 30 Scheme 1 a a Reagents, reaction conditions, and yields: (i) 2-chloro-1,3,2-dioxaphospholane-2-oxide, triethylamine, 0 °C to RT, 10 h; (ii) trimethylamine gas, acetonitrile, reflux, 48 h, 78%.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…For synthesis of LCA-Tam-PC (2), lithocholic acid−tamoxifen conjugate (5, LCA-Tam) was synthesized as reported earlier. 25 LCA-Tam (5) was then reacted with 2-chloro-1,3,2-dioxaphospholane-2-oxide to produce reactive intermediate (6) along with triethylammonium hydrochloride salt (NEt 3 •HCl) (Scheme 1). The reaction mixture was then filtered through Celite and immediately reacted with trimethylamine gas in a pressure tube.…”

Section: Bioconjugate Chemistrymentioning

confidence: 99%

“…24 It has also been witnessed that tethering of dimethylaminopyridine headgroup to lithocholic acid−tamoxifen conjugate enhanced its cytotoxicity against breast cancer cells. 25 We have recently reported the engineering of bile acid derived phospholipids, 26 their ability to form supramolecular self-assemblies, their interactions with model membranes, 27 and their use for drug delivery. 28 These scaffolds can be used for conjugation of chemotherapeutic drugs and imaging agents.…”

Section: ■ Introductionmentioning

confidence: 99%

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Tethering of Chemotherapeutic Drug/Imaging Agent to Bile Acid-Phospholipid Increases the Efficacy and Bioavailability with Reduced Hepatotoxicity

et al. 2017

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Weakly basic drugs display poor solubility and tend to precipitate in the stomach's acidic environment causing reduced oral bioavailability. Tracing of these orally delivered therapeutic agents using molecular probes is challenged due to their poor absorption in the gastrointestinal tract (GIT). Therefore, we designed a gastric pH stable bile acid derived amphiphile where Tamoxifen (as a model anticancer drug) is conjugated to lithocholic acid derived phospholipid (LCA-Tam-PC). In vitro studies suggested the selective nature of LCA-Tam-PC for cancer cells over normal cells as compared to the parent drug. Fluorescent labeled version of the conjugate (LCA-Tam-NBD-PC) displayed an increased intracellular uptake compared to Tamoxifen. We then investigated the antitumor potential, toxicity, and median survival in 4T1 tumor bearing BALB/c mice upon LCA-Tam-PC treatment. Our studies confirmed a significant reduction in the tumor volume, tumor weight, and reduced hepatotoxicity with a significant increase in median survival on LCA-Tam-PC treatment as compared to the parent drug. Pharmacokinetic and biodistribution studies using LCA-Tam-NBD-PC witnessed the enhanced gut absorption, blood circulation, and tumor site accumulation of phospholipid-drug conjugate leading to improved antitumor activity. Therefore, our studies revealed that conjugation of chemotherapeutic/imaging agents to bile acid phospholipid can provide a new platform for oral delivery and tracing of chemotherapeutic drugs.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Bioconjugate Chemistrymentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Tethering of Chemotherapeutic Drug/Imaging Agent to Bile Acid-Phospholipid Increases the Efficacy and Bioavailability with Reduced Hepatotoxicity

et al. 2017

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“…Cytotoxic property of bile acids can be explored further to generate new potent anticancer amphiphiles for GI cancers, and amphiphilic character of bile acids can be used to generate nanomedicines from these amphiphiles. Interesting chemistry of bile acids also provide the potential to conjugate different anticancer drugs to these amphiphiles for effective therapeutics . Ideal candidate for cancer therapy based on bile acids would be the amphiphiles targeting multiple pathways responsible for cancer, and have the propensity to form nanoparticles that can be targeted at tumor sites.…”

Section: Discussionmentioning

confidence: 99%

Cross‐talk between bile acids and gastrointestinal tract for progression and development of cancer and its therapeutic implications

2015

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Increasing incidences of gastrointestinal (GI) cancer are linked to changes in lifestyle with excess of red meat/fat consumption, and elevated secretion of bile acids. Bile acids are strong signaling molecules that control various physiological processes. Failure in bile acid regulation has detrimental effects, often linked with development and promotion of cancer of digestive tract including esophagus, stomach, liver, and intestine. Excessive concentration of bile acids especially lipophillic secondary bile acids are cytotoxic causing apoptosis and reactive oxygen speciesmediated damage to the cells. Resistance to this apoptosis and accumulation of mutations leads to progression of cancer. Cytotoxicity of bile acids is contingent on their chemical structure. In this review, we discuss the chemistry of bile acids, bile acid mediated cellular signaling processes, their role in GI cancer progression, and therapeutic potential of synthetic bile acid derivatives for cancer therapy. V C 2015 IUBMB Life, 67(7): [514][515][516][517][518][519][520][521][522][523] 2015

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“…7 Therefore, although all bile acids are involved in the emulsification of fats, the signaling roles of bile acids in biological processes like cancer cell proliferation, 12 inflammation, 3,13 and apoptosis 14 are contingent on the nature of the bile acids. [15][16][17] Angiogenesis is the process of formation of new blood vessels from existing blood vessels and it is a critical component of cancer progression, tissue repair, and wound healing. 18 Although the role of bile acids in regulation of tumorigenesis 19 and hepatic injury 20 is known, their influence on angiogenesis remains poorly characterized.…”

Section: Introductionmentioning

confidence: 99%

Deciphering the role of hydrophobic and hydrophilic bile acids in angiogenesis usingin vitroandin vivomodel systems

et al. 2017

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Bile acids have emerged as strong signaling molecules capable of influencing various biological processes like inflammation, apoptosis, cancer progression and atherosclerosis depending on their chemistry. In the present study, we investigated the effect of major hydrophobic bile acids lithocholic acid (LCA) and deoxycholic acid (DCA) and hydrophilic bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA) on angiogenesis. We employed human umbilical vein endothelial cells (HUVECs) and zebrafish embryos as model systems for studying the role of bile acids in angiogenesis. Our studies revealed that the hydrophilic CDCA enhanced ectopic vessel formation as observed by the increase in the number of sub-intestinal vessels (SIVs) in the zebrafish embryos. The pro-angiogenic role of CDCA was further corroborated by vessel formation studies performed with human umbilical vein endothelial cells (HUVECs), whereas the hydrophobic LCA reduced tubulogenesis and was toxic to the zebrafish embryos. We validated that CDCA enhances angiogenesis by increasing the expression of vascular growth factor receptors (VEGFR1 and VEGFR2) and matrix metalloproteinases (MMP9) and by decreasing the expression of adhesion protein vascular endothelial cadherin (VE-cadherin). Our work implicates that the nature of bile acids plays a critical role in dictating their biological functions and in regulating angiogenesis.

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Nature of the charged head group dictates the anticancer potential of lithocholic acid-tamoxifen conjugates for breast cancer therapy

Abstract: Anticancer drug Tamoxifen is modified to charged lithocholic acid derived amphiphile for enhanced cytotoxicity against breast cancer cells.

Cited by 13 publications

References 41 publications

Tethering of Chemotherapeutic Drug/Imaging Agent to Bile Acid-Phospholipid Increases the Efficacy and Bioavailability with Reduced Hepatotoxicity

Tethering of Chemotherapeutic Drug/Imaging Agent to Bile Acid-Phospholipid Increases the Efficacy and Bioavailability with Reduced Hepatotoxicity

Cross‐talk between bile acids and gastrointestinal tract for progression and development of cancer and its therapeutic implications

Deciphering the role of hydrophobic and hydrophilic bile acids in angiogenesis usingin vitroandin vivomodel systems

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