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  • br a Department of Pharmaceutical

    2020-08-12


    a Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY, 11439, USA
    b Department of Pharmaceutical Chemistry, University of Karachi, Karachi, 75270, Pakistan
    c Department of Chemistry, University of Karachi, Karachi, 75270, Pakistan
    Keywords:
    Irinotecan
    Indanone
    Thiazolyl hydrazone
    Anti-cancer
    Cell cycle 
    Colorectal cancer is the third leading cause of cancer related deaths in the United States. Currently, Irinotecan, a topoisomerase I inhibitor, is an approved anti-cancer drug for the treatment of patients with advanced or re-current colorectal cancer. Considering low response rate and events of high toxicity caused by irinotecan, we evaluated a series of thirteen thiazolyl hydrazone derivatives of 1-indanone for their potential antineoplastic activity and four compounds showed promising anti-cancer activity against most of the tested colon cancer cell lines with IC50 values ranging from 0.41 ± 0.19 to 6.85 ± 1.44 μM. It is noteworthy that the compound, N-Indan-1-ylidene-N'-(4-Biphenyl-4-yl-thiazol-2-yl)-hydrazine (ITH-6) is found to be more effective than irinotecan against colon cancer cells, HT-29, COLO 205, and KM 12. Mechanistic studies reveal that ITH-6 arrests these cancer cell lines in G2/M phase of the cell cycle, induces apoptosis and causes an increase in ROS level with a significant reduction in the GSH level. The mechanism of inhibition relates to the inhibition of tubulin poly-merization in the mitotic phase. These findings suggest that ITH-6 is a novel drug candidate for the treatment of colorectal cancer.
    1. Introduction
    Cancer till date remains the most intriguing disease of human po-pulations in terms of its types, progression and treatment (Anreddy et al., 2014; Gupta et al., 2016a, 2018; Kathawala et al., 2015). Despite of the advances in the field of cancer research and translational medi-cine, which has indeed result in higher cure rates for various tumor types, cancer still remains the second leading health challenge, after KPT-8602 related disorders in both developing and developed countries (Gupta et al., 2017a,b; Mokhtari et al., 2012).
    Among malignancies, colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the fourth leading cause of cancer related deaths globally (Arnold et al., 2016). CRC is considered to be an environmental disease, affected by cultural, social and lifestyle practices (Cepowicz et al., 2017). Studies done in the past have shown that endocrine factors and obesity are the two major contributors to an increase in the risk of colorectal cancer (Albanes, 1990). Moreover, weight gain during the middle age and metabolic dysfunctions can predispose to abdominal obesity which positively correlates with col-orectal cancer (Kono et al., 1999). It has also been found that the
    Corresponding author.
    dietary habits influence the risk of colorectal cancer. The dietary fat especially from animal sources has earlier been demonstrated to be metabolized into a carcinogen by colonic flora (Moore and LaMont, 1984). Moreover, the genetic makeup of individuals also plays an im-portant role in its genesis and mutations in chromosome 18q have re-sulted in errors in DNA replication which account for 15–20% of sporadic colon cancer (Gryfe et al., 2000; Wynder and Shigematsu, 1967). r> According to the American cancer society, around 135,430 CRC cases were diagnosed in 2017 in the United States with around 50,260 deaths estimated from the disease (Siegel et al., 2017). Studies have shown that approximately 30% of colorectal cancer cases are hereditary in nature (O’Brien, 2000). The etiology remains unknown for around 75% cases of CRC and the remaining small percentage of cases are due to familial incidences or inflammatory bowel disease. Around 33% of familial cases have a genetic basis (Hisamuddin and Yang, 2004). Surgery is the primary treatment option KPT-8602 for most cases of colorectal cancer (Compton, 2003). The current pharmacological management of primary colorectal cancer is based on the drug regimens such as FOLFOX and FOLFIRI for metastatic CRC. Though therapeutically
    S. Narayanan, et al.
    efficacious, these anti-cancer agents bear a number of side effects such as nausea, vomiting, neurotoxicity, and infections which frequently reach to the level of causing a halt of the treatment (Schuell et al., 2005; Wiela-Hojeńska et al., 2015). Targeted specific drugs such as regor-afenib, cetuximab, and bevacizumab have now been approved as al-ternatives for the treatment of CRC (Wang et al., 2017; Mirone et al., 2016). Although these drugs are effective and increase the overall survival, the existence of drug resistance mechanisms and toxicity re-main serious concerns (Anreddy et al., 2014; Kathawala et al., 2015).