Abstract
2-Methoxyestradiol (ME), one of the most widely investigated A-ring-modified metabolites of estrone, exerts significant anticancer activity on numerous cancer cell lines. Its pharmacological actions, including cell cycle arrest, microtubule disruption and pro-apoptotic activity, have already been described in detail. The currently tested d-ring-modified analogue of estrone, d-homoestrone, selectively inhibits cervical cancer cell proliferation and induces a G2/M phase cell cycle blockade, resulting in the development of apoptosis. The question arose of whether the difference in the chemical structures of these analogues can influence the mechanism of anticancer action. The aim of the present study was therefore to elucidate the molecular contributors of intracellular processes induced by d-homoestrone in HeLa cells. Apoptosis triggered by d-homoestrone develops through activation of the intrinsic pathway, as demonstrated by determination of the activities of caspase-8 and -9. It was revealed that d-homoestrone-treated HeLa cells are not able to enter mitosis because the cyclin-dependent kinase 1-cyclin B complex loses its activity, resulting in the decreased inactivation of stathmin and a concomitant disturbance of microtubule formation. However, unlike 2-ME, d-homoestrone does not exert a direct effect on tubulin polymerization. These results led to the conclusion that the d-homoestrone-triggered intracellular processes resulting in a cell cycle arrest and apoptosis in HeLa cells differ from those in the case of 2-ME. This may be regarded as an alternative mechanism of action among steroidal anticancer compounds.
Highlights
The global burden of cancer is continuing to rise, largely because of the ageing and growth of the world’s population and the increasing adoption of cancer-causing behaviour, such as smoking and physical inactivity, within economically developing countries
Since 1977, when zur Hausen published his results, it has been known that human papillomavirus (HPV) infection is a fundamental causative factor of cervical cancer [4]
human cervical cancer cells (HeLa) cells were grown in DMEM supplemented with 10% heat-inactivated foetal calf serum, 1% non-essential amino acids and 1% penicillin–streptomycin in a humidified atmosphere containing 5% CO2 at 37°C
Summary
The global burden of cancer is continuing to rise, largely because of the ageing and growth of the world’s population and the increasing adoption of cancer-causing behaviour, such as smoking and physical inactivity, within economically developing countries. Cancer is the second leading cause of death both worldwide and in economically developed countries [1]. All types of tumours that affect the reproductive organs (breast, uterus, cervix and ovaries) are to be found in the list of the 10 most frequently diagnosed cancers [2]. Cervical cancer is the second most commonly diagnosed cancer, affecting the reproductive system in females throughout the world. It accounted for some 8% of the total new cancer cases and 7.5% of. The therapeutic interventions include radical surgery, brachytherapy and in most cases platinum-based chemotherapy or a combination of these [6]. As concerns the therapeutic difficulties involved in the treatment regimens, adverse effects including haematological and gastrointestinal toxicities or the lack of a significant improvement in survival rate have been reported in connection with cisplatin, in spite of promising drug and/or radiation a 2015 The Authors
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