Induction of cellular senescence as a novel therapeutic. In paper ii, we explored the potential of pro senescence therapy in melanoma treatment. Schematic view of the approaches that are readily available for the implementation of prosenescence therapy in cancer treatment. This therapy induced senescence tis has been associated with tumor relapse. Prosenescence therapy by targeting myc and its network as a. The recently approved cdk4 and cdk6 inhibitor palbociclib has demonstrated that pro. Further, cell nonautonomous senescence responses may contribute to therapy resistance in certain circumstances. Exploiting tumor cell senescence in anticancer therapy. Therefore, drug discovery which selectively induces senescence in cancer cells could represent a promising approach for cancer intervention, through a process called pro senescence therapy 7, 39, 63.
As a potential therapeutic goal, tis might contribute to developing a pro. Hormone therapy for prostate cancer chemotherapy for prostate cancer immunotherapy for prostate cancer treating prostate cancer spread to bones common treatment approaches treatments for prostate cancer are generally used one at a time, although in some cases they may be combined. Ovarian cancer is the most lethal gynecological malignancy and the fifth leading cancer related cause of death among women in the united states. Pdf prosenescence therapy for cancer treatment researchgate. As most studies show that even after efficient cancer therapies minimal residual disease persists, we suggest that therapies should include immunemediated senescence for cancer surveillance. Chronic treatment with ginsenoside rg3 induces aktdependent. Identification of novel druggable targets that regulate senescence in pten null tumors would help in developing prosenescence compounds for the treatment of different types of cancer. It is acknowledged that cancer cells are able to undergo senescence in response to clinically used chemotherapeutics. Ois, in which aphidicolin treatment results in the abrogation of senescence 28.
Therefore, inactivation of pten in cancer cells would be an attractive way of prosenescence therapy. Roles of apoptosis and cellular senescence in cancer and. Diversity of the senescence phenotype of cancer cells treated. The first prosenescence drugs for cancer treatment are now a clinical reality, but still few targets. Noncellautonomous regulation of cellular senescence in cancer. Our expanding knowledge of the senescence mechanism will help to advance pro senescence cancer therapy, so that it can reach the clinic as a cancer therapy in the near future. This form of cellular senescence is unrelated with the shortening of telomeres and the generations of proliferation. Induction of cellular senescence as a novel therapeutic strategy for melanoma treatment abstract oncogeneinduced senescence ois is a welldocumented phenomenon both in vitro and in vivo as a tumorsuppression mechanism. Senescence inducer shikonin rosdependently suppressed lung. Frontiers noncell autonomous effects of the senescence. Prosenescence therapy apoptosis senescence apoptosis senescence cancer growth cancer growth arrest cancer cells oncogenic pathways shp2 oncogenic pathways shp2i figure 1. Polyphenols are natural compounds with anti cancer properties and their application is a considerable choice.
The prosenescence activity of ir was also confirmed in other p53 wildtype cells, including. Keeping cancer cells in a nonproliferating state is a strategy, which directly copes with the lost homeostasis of aggressive tumors. A chemogenomic screening identifies ck2 as a target for pro. Cancer cells use oncogenic pathways to silence the apoptotic and senescence programs. Tis was also evident in human breast cancer samples taken from patients who.
Cellular senescence is a permanent growth arrest that is broadly recognized to act as a barrier against tumorigenesis. The current revolution in cancer treatmentcancer immunotherapyis based on the mobilization of the immune system to target cancer cells and is opening new avenues for achieving cancer control. Importantly, evidences indicate that cellautonomous mechanisms, such as genetic alterations or therapeutic interventions targeting specific genetic. Senescence was induced in various cancer cell lines a549. May 23, 2018 lung adenocarcinoma lac, predominant subclassfication of lung cancer, leads high incidence and mortality annually worldwide. This senescent response, termed therapy induced senescence tis, relies on engagement of the p16 and p53 tumor suppressor networks. Manipulation of senescence pathways for cancer therapy. Many standard cytotoxic dnadamaging therapies aimed at killing cancer cells have the unintended consequence of inducing senescence, which is also known as therapy induced senescence tis. Therefore, inactivation of pten in cancer cells would be an attractive way of pro senescence therapy.
Finally, we propose several therapeutic strategies that allow for the inclusion of prosenescence therapy as part of cancer treatment protocols. In summary, the current study lan et al, 2015 provides a timely target for prosenescence cancer therapy. Cellular senescence, geroscience, cancer and beyond. Dissecting pharmacological effects of chloroquine in cancer. Nevertheless, the role of senescence in tumorigenesis is controversial and few senescence inducers are extensively.
Inhibitors are shown in red boxes and target proteins in blue ovals. Here we provide an overview of mechanisms by which cellular senescence plausibly contributes to therapy resistance and concepts by which senescence responses can be influenced to improve cancer treatment outcomes. Pro senescence therapy is a recently proposed anti cancer strategy and has been shown to. Genetic models in which either of these networks is inactivated show resistance to cancer treatment, directly linking the ability to mount a robust senescence response.
Interestingly, the presence of senescence hallmarks in treated ovarian tumors predicted beneficial outcomes in patients, suggesting that senescence biomarkers could help inform cancer treatment strategies and that senescence becomes a target for pharmacological manipulation in human ovarian cancer therapy. Cellular senescence and cancer chemotherapy resistance. Although therapyinduced senescence tis was first described in tumour cell lines. Identification of ribonucleotide reductase m2 as a potential. Cytokineinduced senescence for cancer surveillance.
While from an evolutionary perspective senescence is beneficial in that it protects against malignancies, the accumulation of senescent cells in tissues and. Narita m, nunez s, heard e, narita m, lin aw, hearn sa, spector dl, hannon gj, lowe sw. Normal cells accumulate the alterations from dna damage, oxidative stress, and oncogene stress that trigger an. Cellular senescence and anticancer therapy bentham science. The first prosenescence drugs for cancer treatment are now a clinical reality, but still few targets have been identified whose inactivation results in cancer cell senescence. During the premalignant transition from lung adenomas to lac, cellular senescence is regard as a critical physiological barrier against tumor progression. Jun 24, 2011 schematic view of the approaches that are readily available for the implementation of pro senescence therapy in cancer treatment. However, given the complex nature of both cellular senescence and cancer, as well as the various pros and cons of each. Senescence stable cell cycle arrest limits the development of cancer, raising the possibility that selectively enhanced senescence in cancer. Measuring aging and identifying aging phenotypes in cancer. Jun 18, 2015 these findings substantiate the pro senescence potential of cx4945 in a genetically engineered mouse prostate model and identify a novel effective pro senescence compound for prostate cancer therapy. The first pro senescence drugs for cancer treatment are now a clinical reality, but still few targets. Is there a differential impact on the rate of aging that depends more on the type and stage of the cancer and less on the therapy. We argue that the availability of pro senescence therapy could represent as a promising regimen for managing cancer disease, particularly with regard to the poor clinical outcome obtained with other anticancer therapies.
However, diploid cells can also experience an accelerated senescence response, termed premature. Can these individualsgroups be identified and studied. Chemotherapyinduced cellular senescence suppresses. Hence, the concept of prosenescence therapy has emerged as an alternative of anticancer therapy, especially for tumors resistant to apoptosisinducing therapies or where conventional therapies cause severe sideeffects. Cancer is one of the most serious diseases endangering human health. In paper ii, we explored the potential of prosenescence therapy in melanoma treatment. Cellular senescence in the treatment of ovarian cancer. Hence, the concept of pro senescence therapy has emerged as an alternative of anti cancer therapy, especially for tumors resistant to apoptosisinducing therapies or where conventional therapies cause severe sideeffects. This will allow for an effective evaluation in the clinic of drugs that modulate picsinducing and pics. It functions as a barrier to tumor initiation and progression. Oct 14, 2014 several novel strategies have been developed to promote senescence in tumours. Therapies for patients with advanced cancer generally include surgical tumor resec.
Jci a novel type of cellular senescence that can be. Findings from the senescence research field suggest the possibility of harnessing the tumorsuppressive potential of senescence, giving rise to the hypothesis that prosenescence therapy involving the induction of a fixed cytostatic condition could be an effective way to. The senescence associated secretory phenotype sasp is a hallmark of tis and may contribute to aberrant effects of cancer therapy. In conclusion, we believe that pro senescence therapy for cancer is a promising new therapeutic strategy and that in the future novel, therapies based on senescence induction in cancer will be the standard of care for the treatment of cancer patients. Cellular senescence is a stable cell cycle arrest that occurs in diploid cells during aging. Among the most promising pro senescence therapies for cancer there are compounds that can enhance or reactivate p53 in tumours, that blocks the cell cycle machinery and inhibit telomerase. The sasp, a plethora of largely proinflammatory cytokines and chemokines, accounts for the complex crosstalk that senescent cells engage in. Dec 21, 2018 a large increase in the incidence of cancers has been predicted for the coming years, with the number of cases worldwide rising from 15 million to 24 million between 2015 and 2035 1 1. Damaged cells at risk of neoplastic transformation can be neutralized by apoptosis or engagement of the senescence program, which induces permanent cellcycle arrest and a bioactive secretome that is implicated in tumor immunosurveillance. Do accelerated aging trajectories differ by cancer treatment, cancer populationage group, etc 20. Prosenescence therapy is a recently proposed anticancer strategy and has been. The dynamic nature of senescence in cancer nature cell biology. Moreover, recent years have provided evidence that some drugs can selectively remove senescent cells.
In view of the side effects caused by chemotherapy and radiotherapy, it is necessary to develop lowtoxic anti cancer compounds. The recent discovery that various anticancer agents, including canonical inducers of apoptosis, act also as inducers of cellular senescence indicates that pro senescence strategies may have applications in cancer prevention therapy. In conclusion, we believe that prosenescence therapy for cancer is a promising new therapeutic strategy and that in the future novel, therapies based on senescence induction in cancer will be the standard of care for the treatment of cancer patients. Jun 03, 2015 in summary, the current study lan et al, 2015 provides a timely target for pro senescence cancer therapy. Sixth, the elucidation of the molecular requirements underlying pics has allowed us to identify a number of critical entry points for the rationale development of a pro senescence therapy for cancer chemoprevention and treatment figure 5i. Therefore, pro senescence therapy will have to be applied in a highly specific manner in the clinic and might require initial genotyping before use. However, the use of these inhibitors in the clinic has been limited by their poor tolerability in cancer patients nardella, nat rev cancer 2011. This approach has been named pro senescence therapy for cancer. Apr 27, 2015 in summary, the current study lan et al, 2015 provides a timely target for pro. Rbmediated heterochromatin formation and silencing of e2f target genes during cellular senescence. Senescence is predominant in premalignant tumors, and senescence escape is thought to be required for tumor progression. The recently approved cdk4 and cdk6 inhibitor palbociclib has demonstrated that prosenescence therapies are effective against breast cancer, and inhibitors of shp2 could well join the ranks in the near future. Pdf abundant evidence points to a crucial physiological role for cellular senescence in combating tumorigenesis.
Here, we propose that the sasp may also serve as a major driver of escape from senescence and the reemergence of proliferating tumor cells, wherein factors secreted from the senescent cells contribute to the. Senescent cells and their secretory phenotype as targets for. Apr 25, 2018 ovarian cancer is a radiosensitive tumor40. This, and its promising preclinical results, make cq an outstanding candidate for repurposing in cancer treatment.