Raloxifene and bazedoxifene as selective ALDH1A1 inhibitors to ameliorate cyclophosphamide resistance: A drug repurposing approach

Narendra, Gera; Raju, Baddipadige; Verma, Himanshu; Kumar, Manoj; Jain, Subheet Kumar; Tung, Gurleen Kaur; Thakur, Shubham; Kaur, Rajdeep; Kaur, Satwinderjeet; Sapra, Bharti; Singh, Pankaj Kumar; Silakari, Om

doi:10.1016/j.ijbiomac.2023.124749

Cited by 3 publications

(3 citation statements)

References 47 publications

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“…These active metabolites facilitate CP's biological function. 12 Hepatic aldehyde oxidase may also detoxify CP, producing carboxyphosphamide and 4-ketocyclophosphamide. 13 According to Swystun et al, 14 the cytotoxic effects of CP are dose-dependent and gradually eliminated from the body.…”

Section: Metabolism Of Cpmentioning

confidence: 99%

Cytotoxic Properties of Cyclophosphamide: A Focus on Its Mechanistic Impacts on Male Gonadal Functions

Olowe,

Oyovwi,

Nwangwa

et al. 2024

J Explor Res Pharmacol

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Cyclophosphamide (CP) is a potent chemotherapeutic agent utilized in the treatment of various types of cancer. However, in addition to its efficacy in combating cancer, CP also has severe side effects, including damage to male gonadal functions. This paper aims to explore the cytotoxic properties of CP and its mechanistic impacts on male gonadal functions. The search strategy was conducted using several reviewed articles indexed in PubMed, Science Direct, EBSCO, Scopus, Cochrane Library, Sage Journals, and Google Scholar. CP is an alkylating agent that damages cancer cell DNA, inhibiting growth and division. It also affects healthy cells, leading to severe cytotoxicity. In male gonadal tissues, CP damages germ cells, Leydig cells, and Sertoli cells, causing decreased sperm count, testosterone levels, and disruption of the blood-testis barrier. The metabolism of CP in the liver generates reactive oxygen species, leading to oxidative damage and cell death. Moreover, CP also affects the hypothalamic-pituitary-gonadal axis, regulating male gonadal functions. CP disrupts the production and secretion of gonadotropin-releasing hormone, follicle-stimulating hormone, and luteinizing hormone, resulting in a decrease in testosterone levels and impaired spermatogenesis. Additionally, CP exerts its cytotoxic effects by inhibiting the proliferation and differentiation of germ cells, leading to a decrease in sperm production. It also affects Leydig cells, which are responsible for the production of testosterone, thus decreasing testosterone levels. In conclusion, CP exhibits potent cytotoxic properties that not only affect cancer cells but also severely damage male gonadal functions. The mechanisms involved in CP-induced gonadal toxicity include oxidative stress and disruption of the hypothalamic-pituitary-gonadal axis. Therefore, it is crucial to consider the potential gonadal toxicity of CP when prescribing it for cancer treatment and to closely monitor the gonadal functions of male patients

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Section: Metabolism Of Cpmentioning

confidence: 99%

Cytotoxic Properties of Cyclophosphamide: A Focus on Its Mechanistic Impacts on Male Gonadal Functions

Olowe,

Oyovwi,

Nwangwa

et al. 2024

J Explor Res Pharmacol

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“…1, the conversion of CP to PM is diverted at the level of aldophosphamide by converting it into inactive carboxyphosphamide using tumoral overexpressed ALDH1A1. 5,6 This ultimately leads to chemoresistance and tumor relapse. 6 Various mechanisms are responsible for the overexpression of ALDH1A1 in tumor cells, including proteinprotein interactions, genetic variations, and transcription factors.…”

Section: Introductionmentioning

confidence: 99%

Scaffold hopping based designing of selective ALDH1A1 inhibitors to overcome cyclophosphamide resistance: synthesis and biological evaluation

Narendra,

Raju,

Verma

et al. 2024

RSC Med. Chem.

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“…Apart from developing new drugs, repurposing older ones appears sustainable and inexpensive. Repurposing of licensed drugs as therapeutics for infectious and non-infectious diseases is rising extensively. − It promises to bring potentially life-saving treatments that are less expensive and faster along the development pipeline. However, even a repurposed drug will require validation through a fresh clinical trial to avoid side effects.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Targeting of Lung Adenocarcinoma with Mannose-Coated Chitosan/Copper Nanocluster–Levocetirizine Nanocomposite

Choudhury,

Chattopadhyay,

Ghosh

2023

ACS Appl. Nano Mater.

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Lung adenocarcinoma is regarded as the most common form of lung cancer, per the latest epidemiological data. The combined efforts from chemotherapy and radiotherapy have done little to increase survival rates. Thus, repurposing licensed drugs has become a feasible approach to filling such gaps. Levocetirizine dihydrochloride, a common antihistamine, has been loaded into copper nanoclusters. The subsequent levocetirizine loaded copper nanoclusters were loaded into mannose functionalized chitosan nanoparticles. This therapeutic module has been established to target lung adenocarcinoma cells in both the monolayer and tumor spheroids. The nanocomposite was found to be inherently fluorescent, biocompatible, and water-soluble. The drug release profile was found to be pH-dependent, with maximum release in the acidic medium. Experimental results concluded efficient cellular localization followed by significant antiproliferative activity. Subsequent functional assays revealed suggestive reactive oxygen species generation, membrane potential depolarization, and reduced lipid droplets leading up to apoptosis. A remarkable reduction in colony formation and migration capacity was also observed. They also inhibited the spheroids of both A549 and HeLa cells. Briefly, the as-synthesized nanocomposites showed a promising scope as an anticancer treatment approach.

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Raloxifene and bazedoxifene as selective ALDH1A1 inhibitors to ameliorate cyclophosphamide resistance: A drug repurposing approach

Cited by 3 publications

References 47 publications

Cytotoxic Properties of Cyclophosphamide: A Focus on Its Mechanistic Impacts on Male Gonadal Functions

Cytotoxic Properties of Cyclophosphamide: A Focus on Its Mechanistic Impacts on Male Gonadal Functions

Scaffold hopping based designing of selective ALDH1A1 inhibitors to overcome cyclophosphamide resistance: synthesis and biological evaluation

Therapeutic Targeting of Lung Adenocarcinoma with Mannose-Coated Chitosan/Copper Nanocluster–Levocetirizine Nanocomposite

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