8.9 Cancer Treatments Targeting Apoptosis/Senescence

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Introduction

 

Cancer cells are able to strategically evade the normal cellular mechanisms of apoptosis and senescence in order to continue proliferating in an unrestricted manner. This gives them the ability to grow past their Hayflick limit, thus entering a phase of limitless reproductive potential. It is no surprise that much of the research efforts thus far has focused, and continues to focus, on restoring these two important processes. Current therapeutic approaches not only target abnormal cell proliferation, but also incorporate tactics that make it more difficult for abnormal cells to survive. This section highlights some of the key apoptotic and senescent targets in modern cancer research.

 

Apoptotic-based Cancer Treatments


Curcumin
 

Predictably, most modern cancer treatments and drugs aimed against apoptosis target the key players in the apoptotic pathways. One strategy has been to target the anti-apoptotic Bcl-2 family of proteins to inhibit the expression of their genes and thereby increase apoptosis (1). Treatment approaches include the use of Bcl-2 specific siRNA, protein antagonists, and inhibitors of Bcl-2 gene expression (1). One recent example is the compound Curcumin, which has been found to inhibit the growth of lung cancer cells by downregulating the levels of Bcl-2 protein (2).

 

Curcumin, or diferuloylmethane, is a principle component in the spice tumeric. In vitro studies have shown that it is a chemical capable of interacting with components of pathways involved in inflammation, for example by down regulating, cyclo-oxygenase 2, lipoxygenase and  inhibition of several other inflammatory enzymes (14). It has also been shown, in preclinical trials, to have an anti-invasive, anti-proliferative and antiangiogenic effect. However, this function has yet to be demonstrated in clinical trials on humans. Curcumin is being study for the treatment of multiple types of cancers, arthritis, Alzheimers disease, Parkinson disease, cardiovascular disease,  among many others (14). Unfortunately, the bioavailability of curcumin is limited due to its poor absorption and rapid metabolism upon entry to the body.  It has also been shown that curcumin can have carcinogenic effects, by interference with the p53 pathway (13).  Curcumin has cytotoxic effects and induces apoptosis in breast cancer (15). However, this mechanism is not fully understood. While p53 and bcl-2 get downregulated via curcumin bioactivity, protein expression of proteins p21 and bax increased and cells were arrested in G2/M (15). 

 

Another target of therapies has been activation of the p53 pathway due to its central role in cell cycle arrest (3). The loss of the p53 tumour suppressor gene can be treated through gene therapy. The basic idea behind gene therapy is to deliver the fully functional "wild type" p53 gene or protein into cells to compensate for the mutant copies. The wild type p53 gene can be delivered into cells with a retrovirus, thus restoring it. Another way of re-introducing p53 is thorugh vaccinations, a type of cancer immunotherapy (1).


Survivin and Apomab

A third target is the inhibitor of apoptosis proteins (IAPs). The goal here is to suppress the inhibition of caspases in the intrinsic and extrinsic pathways that would otherwise kill the cancer cell (3). Again, antisense oligonucleotides, targeted siRNAs, and peptidic or non-peptidic IAP antagonists have been found to be successful in restoring caspase activities in the apoptotic process (1). As an example, a key IAP protein target discovered in recent years is Survivin, which inhibits caspase-9 and promotes chemoresistance. Survivin can be suppressed with wild-type p53, retinoblastoma, and siRNA targeting, among other mechanisms (4).

 

Survivin, also known as baculoviral inhibitor of apoptosis repeat-containing 5 or BIRC5, is a human protein encoded by the BIRC5 gene (16). As an inhibitor of caspase activation, this cell inducing negative regulation of programmed cell death. Disrupting pathways which involved survivin by targetting survivin specifically can lead to increased tumor apoptosis and increased tumor death. Different studies have shown that Survivin is inhibits Bax and Fas induced apoptoic pathways, and also interacting with caspase-3 & caspase-7 by inhibiting their processing into active forms (16). Survivin is a great target for cancer therapies as it is not present in high quanitites in regular human tissue but rather prevalent in only tumors and fetal tissue; making it a great tumor biomarker as well. Being that it is only expressed in G2/M phase, Survivin is highly regulated by the cell cycle. Survivin has been associated with the mitotic spindle during mitosis, the tumour suppressor protein p53, the Wnt pathway and beta-catenin (16). 

 

Targets specific for the extrinsic apoptosis pathway include the death receptors DR4 and DR5 (12). One proapoptotic receptor agonist for these receptors is apoptosis ligand 2/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL). When cells are subjected to this agonist, it binds to the cell surface death receptors to activate them, initiating the death-induced signaling complex (DISC) through recruitment of caspases (12).  The Apo2L/TRAIL has great potential for treating cancers because this pathway has been found to be intact in several cancerous cells and does not rely on p53 in order to function (12). It has also been shown experimentally that a recombinant human Apo2L/TRAIL soluble protein can activate both receptors (12). Hopefully, tumor cells resistant to the standard forms of chemotherapy can be killed by the action of such agonists that target DR4 and DR5 independently or together with chemotherapy.  A second proapoptotic receptor agonist is a monoclonal DR5 agonist antibody called Apomab, which acts by selectively inducing apoptosis in cancerous cells, without affecting normal cells (12).  Treatment with other monoclonal antibodies is also possible, which are capable of activating either DR4 or DR5. (12). 

 

The checkpoint kinases, Chk1 and Chk2, are the final targets. The regulation of these proteins are central to the arrest cell cycle progression at the S and G2/M checkpoints in response to DNA damage (5). By using inhibitors of these two kinases along with chemotherapies, researchers hinder the critical ability of cancer cells to repair damaged DNA at these checkpoints. There have been numerous successes in preclinical trials for drugs that perform this function (5).

 

 

Future Directions for Cancer Treatment Involving Apoptosis

 

Existing evidence of successful cancer treatment strategies involving apoptotic pathways as targets shows that further treatment tactics along these lines should continue to be explored in many types of cancer. Based on the trend, future strategies might incorporate current chemotherapies in combination with apoptosis-targeting drugs to enhance existing efforts (1). However, these therapies should be subjected to thorough experimentation before embarking on clinical trials. One of the main issues is that we do not fully understand how the growth and proliferation of normal cells will be affected through the course of apoptosis therapy. The specificity of apoptosis drugs to targeting cancer cells alone is a challenge. Many current drug treatments in this area remain in preclinical and research stages, so exploring the specificity of new drugs to the apoptotic pathways in cancer cells must continue to be emphasized (5).

 

 

 

Senescence-based Cancer Treatments

 

As mentioned before, senescence is an age-related, naturally occurring cellular process that turns off cell growth. Like apoptosis, senescence is tightly controlled through a number of mechanisms that can be targeted for treatment. Aside from apoptosis, cancer cells have to evade senescence in order to continue proliferating. One important fact to note is that many tumor cells retain the ability to senesce, even if carcinogenic activity has made it significantly harder to do so (6).

 

Re-expressing Tumour Suppressor & Senescence Genes

 

One major approach to stimulating senescence in cancer cells is through genetic modifications. Examples include:

  • Activating senescence-determining genes, like MORF4
  • Using viral proteins such as papillomavirus protein E2 to revive p53 and pRb (tumour suppressor) activity

The idea behind these treatments is to use the forced expression of tumor suppressor genes researchers to push cancer cells into senescence (6). This has successfully been done with genes such as p53, pRb, p16, and p21, effectively arresting the growth of cancer through and achieving senescence (7).

 

DNA Damage Induced-senescence

 

Cellular senescence is a well characterized response to DNA damage. Therefore, it follows that an alternative treatment strategy direction involves inducing DNA damage in tumor cells through chemotherapy, radiation, and retinoids (7). Along with ionizing radiation, the most effective chemotherapeutic drugs for inducing senescence are those that attack DNA structure. The most notable examples are doxorubicin, cisplatin, and aphidocolin (6). Additionally, retinoids, derived from Vitamin A, have been found to be capable of inducing a state of stable growth arrest that phenotypically resembles senescence (6).

 

Targeting Telomerase

 

Finally, of the most notable treatment strategies centers on the inhibition of telomerase. The relationship between telomerase activity and cancer growth has long been established. Normal somatic cells express relatively low levels of telomerase, whereas cancerous cells express high levels of the enzyme, especially those found in advanced tumours. Countless reports in the literature have shown increased telomerase activity in a variety of human carcinomas. It is also known that telomere extension plays a crucial role in immortalization of the cancer cells (8). Cancers with overactive telomerase continue to grow and bypass senescence. For all these reasons, blocking telomerase activity is a logical anti-cancer target. Unfortunately, telomerase treatment remains still unproven in some cancer, in terms of efficacy, and is subject to ongoing development.

 

Telomerase inhibition has been approached using:

  • Specific antisense RNA 
  • Catalytically inactive telomerase reverse transcriptase
  • Transfection with mutated template RNA (9). 

 

 

Future Directions for Cancer Treatment Involving Senescence

 

Future strategies employing senescence in cancer treatment will evolve as understanding of senescence-inducing pathways and genes increases. Combination therapy involving chemotherapy, radiation, and retinoids should also continue to be used in concert with DNA-damaging drugs as they are isolated (11). With telomerase targeting, researchers are looking to increasingly develop strategies that minimize side effects compared to other existing chemotherapeutic agents, an idea that is already being explored (9). However, with any anti-cancer therapy, there are potential negative side-effects on the body. Interestingly, new studies have reported that the senescent release of inflammatory factors may in fact, favor tumor progression. This is one of many possible consequences of inducing senescence (11). In addition to this, inducing senescence in cancer cells may also cause the acceleration of cellular aging, morphologically. These are other avenues of research that should be explored in the future.

 


 

References

1.      Wong, R.S.Y. (2011). Apoptosis in cancer: from pathogenesis to treatment. Journal of Experimental & Clinical Cancer Research : CR 30, 87.

2.      Wu, S.-H., Hang, L.-W., Yang, J.-S., Chen, H.-Y., Lin, H.-Y., Chiang, J.-H., Lu, C.-C., Yang, J.-L., Lai, T.-Y., Ko, Y.-C., et al. (2010). Curcumin induces apoptosis in human non-small cell lung cancer NCI-H460 cells through ER stress and caspase cascade- and mitochondria-dependent pathways. Anticancer Research 30, 2125–2133.

3.      Gerl, R., and Vaux, D.L. (2005). Apoptosis in the development and treatment of cancer. Carcinogenesis 26, 263–270.

4.      Mita, A.C., Mita, M.M., Nawrocki, S.T., and Giles, F.J. (2008). Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research 14, 5000–5005.

5.      Zhang, H., Xiao, Z., Sowin, T. (2010). Chk1 and Chk2 as Checkpoint Targets. Cancer Drug Discovery and Development, pp. 245-259.

6.      Shay, J.W., and Roninson, I.B. (2004). Hallmarks of senescence in carcinogenesis and cancer therapy. Oncogene 23, 2919–2933.

7.      Roninson, I.B. (2003). Tumor cell senescence in cancer treatment. Cancer Research 63, 2705–2715.

8.      Acosta, J. C., Gil, J. (2011). Senescence: a new weapon for cancer therapy. Trends in Cell Biology, 22, 211-219.

9.      Marin, J. J., Vergel, M. Carnero, A. (2010). Targeting Cancer by Inducing Senescence. The Open Enzyme Inhibition Journal, 3, 46-52.

10.    Herbert, B. S., Wright, W. E., Shay, J. W. (2001). Telomerase and breast cancer. Breast Cancer Research, 3, 146-149.

11.    Campisi, J., di Fagagna, F. d’A. (2007). Cellular senescence: when bad things happen to good cells. Molecular Cell Biology, 8, 729-740.

12.    Ashkenazi A. (2008). Targeting the extrinsic apoptosis pathway in cancer. Cytokine & Growth Factor Reviews. 19: 325-331. 

13. Kawanishi, S; Oikawa, S; Murata, M. (2005). Evaluation for safety of antioxidant chemopreventive agents. Antioxidants & Redox Signaling (11-12): 1728 - 1739

14. Goel A, Kunnumakkara AB, Aggarwal BB (2008). "Curcumin as "Curecumin": from kitchen to clinic". Biochem Pharmacol 75 (4): 787–809

15. Chiu T, Su C (2009). Curcumin inhibits proliferation and migration by increasing the Bax to Bcl-2 ratio and decreasing NFkBp65 expression in breast cancer MDA-MB-231 cells. InT J Mol Med. (4):469-75

16. Tamm I, Wang Y, Sausville E, Scudiero DA, Vigna N, Oltersdorf T, Reed JC (1998). IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases and anticancer drugs. Cancer Res. 58 (23): 5315-20.