ATM kinase inhibitor KU-55933 contribution in cisplatin mediated HeLa proliferation

Abstract

Several approaches including chemotherapy and radiation therapies are being at the forefront to treat various types of cancer including cervical cancer. However, the success and failure of genotoxic based therapy is attributed to aberrant ability of carcin oma to patch up genomic breaks. Here, we have used cisplatin as a genotoxic drug model and HeLa as in vitro carcinoma model due to less responsiveness and resistance of HeLa against cisplatin. Here, attempts are made to investigate the effects of DNA double strand break inhibitor KU-55933 against the cisplatin cell growth and cytotoxicity. Following experiments namely in vitro plasmid DNA metabolizing, Trypan blue dye exclusion, M TT, and PI based Flow cytometery PI assays were conducted to study cell growth and cytotoxicity effects. Based on the cell viability and PI based staining data, results remarked that KU -55933 combined with cisplatin could bring convincing cell growth arrest in HeLa. The reduction in HeLa proliferation was noticed from 70% to 30% in case of KU-55933 added with cisplatin over cisplatin alone. However, we noticed none apoptosis based cell cytotoxicity in case of cisplatin alone or combined with the inhibitors. We also observed significant DNA instability in case of KU-55933 treated HeLa lysates added to plasmid DNA substrate over HeLa lysate without KU-55933 treatment. In conclusion, KU-55933 can potentiate low dose of cisplatin response against HeLa. The effect of KU-55933 may not be attributed due to its enhancing the apoptosis way, rather than through cell growth arrest mechanism due to extensive DNA breaks.

Non-homologous End Joining Inhibitor SCR-7 to Exacerbate Low-dose Doxorubicin Cytotoxicity in HeLa Cells

“…The DDR is defined as an inherent common feature in both normal and carcinoma in the response to genomic lesions and toxic stress 12–14. Both carcinoma and normal cells employ several DNA repair pathways, such as mismatch repair, nucleotide excision repair, base excision repair, homologous recombination, and non-homologous end joining (NHEJ) 10–12. DNA DSB is defined as the principle cytotoxic lesion for ionizing radiation, but it can also be generated by genotoxic drugs 9–14.…”

Differential DNA damaging effects of genotoxic agents from chewing tobacco and gutka

“…In this paper, we report the clear, reliable and efficient extraction of genotoxic agents in DMSO solvent from chewing tobacco and gutka in an appreciable amount. These obtained DMSO extract from chewing tobacco and gutka was subjected to the standard in vitro DNA damage assay with slight modifications [7]. The analysis of plasmid DNA damage data revealed that DMSO extract of chewing tobacco showed extensive DNA damage up to the ten times dilution of used extract (Figure 1).…”

DNA Repair Response Modulation Potentiates Low Dose Cisplatin Effects in HeLa Cells

“…The well-known platinum based drug, cisplatin, is being used from decades for carcinoma treatment including cervical cancer. The major issue concerned with cisplatin as a chemotherapeutic option with excessive over dose leading to drug resistance and patients secondary pathophysiological conditions including secondary tumor [2,5,6,10,14,16,22]. The reasons behind cisplatin resistance and efficacy issues may be due to decreased accumulation of drug inside the cell, altered DNA repair or increased efflux of drug [2,10,14,16,23,24].…”

“…At global level, cervical cancer is considered as the second most happening cancer types [1]. Chemotherapy is one of the therapies of cancer where the chemical compounds are used as drug to target the genes or proteins [2][3][4][5][6][7][8]. There are several compounds used as anticancer drugs such as alkylating agents including platinum based drugs [9][10][11][12][13].…”

“…There are several compounds used as anticancer drugs such as alkylating agents including platinum based drugs [9][10][11][12][13]. In spite of certain success, these treatment options face limitations and huddles such as drug resistance, side effects as nephrotoxicity heart failures and relapse of cancer [6,[9][10][11][12][13]. The mechanism of action of cisplatin revolves around binding at the N7 guanine residue in dsDNA, thereby forming 1, 2 intra-strands [2,[14][15][16][17].…”