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Gynecology and Women’s Health ISSN 2474-7602
Volume 11 Issue 3 - August 2018 DOI: 10.19080/JGWH.2018.11.555811
Introduction A hallmarik feature of autopaghy, defined as an evolutionary catabolic lysosomal process, under a program core of 32 Atg proteins, each with a function in the multi step auto phogos me formation, and a elegant and fine tuned regulatory mechanism; is the dichotomy in the host response in cell survival or cell death. As a protective and prosurvival meehanism contribute to mantain homeostasis [1,2], differentiation and normal tissue cell development, function like a housekeeping and control quality of any insult htat threaten an organism. However, as an hyperactivated state (internal or external stimulus-insult) of self eating can cause serious damage cell/injury, that lastly kill the cell [3,4]. These two sides of the coin in which down stream signaling affects that for one side contibute to the elimination of waster disposal products of the metabolism but for other is a source of nutrients in tumor growth constitute the focus of current and intense research in cáncer therapy.
Autophagy as Therapeutic Target in Cáncer
One aspect of serious concern for human health is that autophagy regulates diverse metabolic pathways that promote tumor proliferation and survival [5,6] which are closely associated with oncogenic activators and tumor suppresors. Autophagy has been implicated in cáncer cell invasión, malignant transformation and cáncer progression and even worse in metástasis [7,8]. The identification of potential targets that can be utilized to disrupt cáncer development, novel methods to enhance targeted cáncer therapies is key to understand the molecular networks integrating metabolic pathways [9,10]. More recent work have demonstrated that autophagy also facilitates celular secretion, a novel function that should be taken in account for treatment and to understand its role in cáncer progression [11,12]. From a therapeutic perspective, understanding whether, when and how
J Gynecol Women’s Health 11(3): JGWH.MS.ID.555811 (2018)
autophagy can harnessed to kill cáncer cells remains challenging and represent a new alternative target to treat tumor resistance . In recent years, intense focus on the pathways linking autophagy and cáncer that are relevant for target identification and on pharmaceuticals that can be utlized to improve cáncer therapy by targeting the autophagic pathways, target apoptotic and autophagic activities, as well as epidermal growth factor receptor signaling pathway [14-16] cytochrome P450, CYP in mitocondria, vacuolar protein sorting 34 (VPs34), or another component important for the promotion of NK cells cytoxicity, down regulation of PI3K mediated PI3K/AKT/mTOR/ p70S6K/ULK [17,18]. The ideal treatement would be targeting autophagy in singleagent therapy to sensitize aggressive cancers that are dependen on autophagy for survival or in combination with therapeutic agents that induce autophagy as a resistance mechanism may be an effective therapeutic strategy to treat cáncer . Likewise the stimulation of autophagy in response to therapeutics can contextually favor or weaken chemorresistance and antitumor immunity. Furthermore, chemotherapy agents induce acute metabolic stress that cáncer cells must overcome for their survival [20,21].
These metabolic stress cues in cáncer cells, in first place, can actívate and cause dependence on the self-cannibalization mechanism of macroautophagy (autophagy hereafter) for the lysosomal turnover and recycling of organelles and proteins for energy and stress survival . Second, acute autophagy/ activation in response to cáncer therapy can potentially lead to refractory tumors resistant to converntional chemotherapy. For example, a specific form of autophagy that targets mitocondria (mitophagy) may also function to promote cell survival by the 001
Journal of Gynecology and Women’s Health clearance of damaged mitocondria that are potential sources of reactive oxygen species (ROS) .
Molecular mechanism underlying autophagy pathways by ROS and autophag in cáncer cells responding to ROS producting agents, which are utilized as a therapeutic modality to kill cáncer cells . Furthermore, the molecular mechanism underlying autophagy pathways by ROS and autophag in cáncer cells responding to ROS producting agents, which are utilized as a therapeutic modality to kill cáncer cells . By another hadn, the apoptotic neutrophils that have phagocytized TRAPs inhibited the proliferation and activaition of CD4+T and CD8+ T cells in a cell contact-and ROS-dependent manner, representing a novel TRAP-mediated mechanism in neutrophils that potentially suppresses the anti-Tumor cell immunity and highlight TRAPs as an important target for future tumor immunotherapy [24-26].
How to Improve Anticancer Therapy. “Depending of the Circumstances”
Targeting for therapeutic approaches in cáncer not only the apoptosis pathways but alternative pathways and this can represent an atractive strategy to improve anti-tumor therapy. For example, it has been showed that autophagy is critical to estrogen receptor positive (ER+) breast cáncer cell survival and the development of anti estrogen resistance. Consequently, new approaches are warranted for targeting autophagy in breast cáncer cells undergoing antiestrogen therapy. Moreover, anticancer therapy should take advantage of the modulatory capacity of pharmacologically active compounds, that can cause cells to swtich from one cell death to another depending of the cellular setting. Since crosstalk has been demonstrated between the autophagy-and proteasome-mediated pathways of protein degradation. The proteosome inhibitor bortezomib affects autophagy and cell survival in antiestrogen-treated ER+ breast cáncer cells [20,27]. This drug at clinically doses, induced a robut death response in ER+ antiestrogen-sensitive and antiestrogen-resistant breast cáncer cells undergoing hormonal therapybortezomib inhibits prosurvival autophagy in addition to the known function in blocking the proteasome, and is cytotoxic to hormonally treated ER+ breast cáncer cells . Inhibition or activation of ER stess relates to autophagy, and how these associated pathways can serve dual functions to promote survival or cell death in cáncer . By combining a proteosome inhibitor like bortezomib with antiestrogen therapy may have therapeutic advantage in the managements of early stage of breast cáncer or it lays out a spectrum of potential pharmacological agents and combinatorial approaches that target these pathways to enhance tumor cell kill . In a similar way, triptolide-induce autophagy has a pro-death effect , requires autophagy-specific genes atg5 or beclin1, and is assciated with the inactivation of the Protein kinase B (Akt)/mammalian target of Rapamycin/p70S6K pathway and the up-regulation of the Extracellular SignalRelated Kinase (ERK)1/2 pathway. Inhibition of autophagy in S2-013 and S2-VP10 cells results in cell death via the apoptotic 002
pathway whereas inhibition of both autophagy and apoptosis rescues cell death [30,31]. Quercetin (a dietary antioxidant), activated autophagy in pancreatic cáncer cells by modulation of Akt-mTOR signaling and hipoxia-induced factor 1 alpha (HIF-1alpha) signaling [32-34]. Preliminary results by us, have found that Bacillus thuringiensis Cry toxins mediated-autophagy induction in human pneumocytes class II (A549), a potential cáncer therapeutic capabiility that deserves further investigation either in-vivo and in-vitro [35-37].
To SNI CONACYT and SEP through the PERFIL PRODEP PROGRAM for financial support.
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