Cell Death, A Hallmark of Cancer

Cell Death, A Hallmark of Cancer

Cancer is a disease that results from the uncontrolled proliferation of a cell, which eventually leads to abnormal tissue growth, organ failure and subsequent death. Cancer progression has recently been defined by 6 biological capabilities acquired during the progressive development of human tumours which can provide a logical framework to better understand the diversity of this neoplastic disease [Hanahan and Weinberg, 2011].

Cell Death

Research over the past twenty years has identified programmed cell death as a natural barrier against uncontrolled cell proliferation leading to tumour formation [Danial and Korsmeyer, 2004]. Signalling pathways trigger the apoptotic machinery in response to various physiological stresses such as UV irradiation,oxidative stress, DNA damage or growth factor withdrawal resulting in the induction of cell death to reduce the collateral damage to surrounding tissue and minimise pro-inflammatory responses [Logue and Martin, 2008]. Resistance to cell death has been identified as a hallmark of cancer due to its ability to promote uncontrolled proliferation, which results in tumourigenesis and resistance to chemotherapy {Hanahan and Weinberg, 2011}.

Platinum based drugs

Platinum-based anti-cancer drugs such as carboplatin and cisplatin have been in wide clinical use to treat many forms of cancer such as ovarian, head, neck and non-small cell lung cancer [Jamieson and Lippard, 1999]. Cisplatin treatment results in the formation of cisplatin-DNA adducts, resulting in the activation of DNA checkpoint pathways. Activation of DNA checkpoint pathways that upregulate the p53 tumour suppressor protein result in cell death. However, p53 is mutated in over 50% of all human tumours, therefore resulting in resistance to cisplatin treatment [Jamieson and Lippard, 1999].

Sustained proliferation

Sustained proliferative growth is another hallmark of cancer [Hanahan and Weinberg, 2011]. Malignant melanoma is a highly aggressive cancer that is highly resistant to cell death induced by conventional chemotherapeutics [Houghton and Polsky, 2002]. Over ~60% of melanomas contain mutations within the B-Raf proto-oncogene, thus leading to activation of cell survival pathways and increasing the threshold required for cell death activation [Sheridan et al.,2008a].

Drug development

Drug development over the past fifteen years has investigated direct activation of cell death pathways. Drugs specifically targeting apoptosis pathway activation such as the BH3-mimetics gossypol, ABT-737 and Obatoclax are currently inclinical trials for the treatment of non-small-cell lung cancer and leukaemia [Storey, 2008].

11th Mar 2021 Sean Mac Fhearraigh

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