Received: 23 April 2018 | Revised: 18 September 2018 | Accepted: 26 September 2018

DOI: 10.1002/ardp.201800128

FULL PAPER

Cytotoxicity of new pyridazin-3(2H)-one derivatives

orchestrating oxidative stress in human triple-negative breast
cancer (MDA-MB-468)

Najat Bouchmaa1,2 | Reda Ben Mrid3 | Youness Boukharsa2 |

Mohamed Nhiri3 | Hassan Ait Mouse1 | Jamal Taoufik2 | M'hammed Ansar2 |
Abdelmajid Zyad1

1 Team of Experimental Oncology and Natural

Substances, Cellular and Molecular Immuno- Abstract
pharmacology, Faculty of Sciences and
Triple-negative breast cancer (TNBC) is a complex and aggressive subtype of breast
Techniques, Sultan Moulay Slimane
University, Beni-Mellal, Morocco cancer characterized by high morbidity and mortality. In the absence of targeted
2 Laboratoryof Medicinal Chemistry, Faculty therapy, only chemotherapy is available in this case of cancer. The current study
of Medicine and Pharmacy,
Mohammed V University, Rabat, Morocco
investigated the antitumor effect of new pyridazin-3(2H)-one derivatives on the
3 Laboratory of Biochemistry and Molecular human TNBC cell line, MD-MB-468. The in vitro cytotoxic activities were investigated
Genetics, Faculty of Sciences and Techniques, using the tetrazolium-based MTT assay. Lipid peroxidation, H2O2 content, and the
Tangier, Morocco
specific activities of antioxidant enzymes were also determined. Two molecules, 6f and
Correspondence 7h, were found to be selectively highly active against tumor cells with IC50 values of
Prof. Abdelmajid Zyad, Team of Experimental
Oncology and Natural Substances, Cellular 3.12 and 4.9 µM, respectively. Furthermore, cells exposed to 6f showed a significant
and Molecular Immuno-pharmacology, Faculty
increase in H2O2 and lipid peroxidation levels, accompanied by a decrease in the
of Sciences and Techniques, Sultan Moulay
Slimane University, B.P: 523 Beni Mellal, enzyme activities of glutathione reductase (GR) and thioredoxin reductase (TrxR). The
Morocco.
cytotoxicity of the compound 6f may improve the therapeutic efficacy of the current
Email: a.zyad@usms.ma, ab.zyad2@gmail.com
treatment for TNBC via the inhibition of GR and TrxR activities.
Funding information
Lalla Salma Foundation: Prevention and KEYWORDS
Treatment of Cancer, Grant number: 09/AP
anticancer agent, cytotoxicity, oxidative stress, pyridazin-(2H)-3-ones, triple-negative breast
2013
cancer

1 | INTRODUCTION
Triple-negative breast cancers (TNBC), which account for 10–17% of
all breast cancers, tend to grow more aggressively than other subtypes,
show relatively early recurrence and intrinsically have poor
[1]
prognosis.
This subtype of breast cancer is characterized by a lack of
expression of both oestrogen and progesterone receptors with
simultaneous absence of human epidermal growth factor 2 (HER2)
receptors.[2,3] Indeed, TNBC tumors are not sensitive to standard
therapies since they do not express the relevant receptors (ER, PR,
HER).[2,4–6] Currently, conventional-targeted breast treatment offers
only limited benefits and might cause additional side-effects; such
treatment leaves them associated with a high rate of local and systemic
relapse.[7] In addition, TNBC is more aggressive than other disease
subtypes with no effective therapeutic targeted has been achieved
neither no specific molecular targets agents are currently available for
their treatment.[8] Indeed, the absence of chemotherapeutic vulner-
abilities have been confirmed by the fact that women with TNBC have
the lower survival rate and the highest incidence of metastatic disease

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