Premium
New orally active DNA minor groove binding small molecule CT‐1 acts against breast cancer by targeting tumor DNA damage leading to p53‐dependent apoptosis
Author(s) -
Saini Karan Singh,
Ashraf Raghib,
Mandalapu Dhanaraju,
Das Sharmistha,
Siddiqui Mohd Quadir,
Dwivedi Sonam,
Sarkar Jayanta,
Sharma Vishnu Lal,
Konwar Rituraj
Publication year - 2017
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.22588
Subject(s) - biology , dna damage , cancer research , apoptosis , cancer cell , cancer , mitotic catastrophe , in vivo , breast cancer , dna , biochemistry , genetics , microbiology and biotechnology
Targeting tumor DNA damage and p53 pathway is a clinically established strategy in the development of cancer chemotherapeutics. Majority of anti‐cancer drugs are delivered through parenteral route for reasons like severe toxicity, lack of stability, and poor enteral absorption. Current DNA targeting drugs in clinical like anthracycline suffers from major drawbacks like cardiotoxicity. Here, we report identification of a new orally active small molecule curcumin‐triazole conjugate (CT‐1) with significant anti‐breast cancer activity in vitro and in vivo. CT‐1 selectively and significantly inhibits viability of breast cancer cell lines; retards cells cycle progression at S phase and induce mitochondrial‐mediated cell apoptosis. CT‐1 selectively binds to minor groove of DNA and induces DNA damage leading to increase in p53 along with decrease in its ubiquitination. Inhibition of p53 with pharmacological inhibitor as well as siRNA revealed the necessity of p53 in CT‐1‐mediated anti‐cancer effects in breast cancer cells. Studies using several other intact p53 and deficient p53 cancer cell lines further confirmed necessity of p53 in CT‐1‐mediated anti‐cancer response. Pharmacological inhibition of pan‐caspase showed CT‐1 induces caspase‐dependent cell death in breast cancer cells. Most interestingly, oral administration of CT‐1 induces significant inhibition of tumor growth in LA‐7 syngeneic orthotropic rat mammary tumor model. CT‐1 treated mammary tumor shows enhancement in DNA damage, p53 upregulation, and apoptosis. Collectively, CT‐1 exhibits potent anti‐cancer effect both in vitro and in vivo and could serve as a safe orally active lead for anti‐cancer drug development. © 2016 Wiley Periodicals, Inc.