Reviewing Leads That Promote Apoptosis-Cancer Treatment Strategies Leads That Promote Apoptosis-Cancer

Apoptosis refers to a series of events which usher the cells into committing suicide in a coordinated manner. The intricate network of pathways works together to execute the cell’s demise. It has been established that cancer cells do not follow orthodox courses but instead, re-design the pathways to circumvent apoptosis. In this article, we review the various molecules which have been isolated for targeting major apoptotic pathways. Out of the many mechanisms that are disrupted, the pathways which mediate cell death are generally the most deranged. Considering the relevance of these apoptotic pathways, some molecules that act on these pathways were studied. The leads covered in this article were selected on the basis of their ability to either induce/ enhance pro-apoptotic signals or to inhibit anti- apoptotic signals. The actions of these leads have been demonstrated in various cancer cell lines. The array of compounds chosen include: and some which are chemically formulated. Bax- Bak, p53, SIRT, STAT, Akt-p13- mTOR pathways which lead to increased auto- demise. Each of these leads have hallmark features that make them attractive as cancer treatment strategies. We propose the utilization of these leads as a part of routine treatment of cancer to enhance the survival of cancer patients. Abbreviations: IAP: Inhibitors of Apoptosis Proteins; AIF: Apoptosis Inducing Factor; TRAIL: TNF-Related Apoptosis Inducing Ligand; TRADD: TNFR1 - Associated Death Domain Protein Akt: Protein kinase-B; DISC: Death Inducing Signaling Complex; Stat: Signal Transducer and Activator of Transcription Proteins FADD: Fas Associated Death Domain; JAK: Janus Kinases PUMA p53 Upregulated Modulator of Apoptosis; NOXA: Phorbol 12 Myristate 13 Acetate Induced Protein mTOR Mammalian Target of Rapamycin; NF-kappa B: Nuclear Factor Kappa - Light Chain - Enhancer of Activated B-cells; ROS: Reactive Oxygen Species


Introduction
Apoptosis is the process by which a cell commits itself to death. Stresses that initiate apoptosis can either be physiological rejection, viruses etc., the changes seen in the architectural framework of apoptotic cells are compaction of chromatin followed by dissolution of the nuclear skeleton, abatement of cellular organelles and the loss of integrity of lipid bilayer which at the end leads to blebbing of the membrane [1]. The death programme is set into motion through two major pathways-intrinsic and extrinsic as depicted in the next section. Figure 1

Disruption of Apoptosis in Cancer
One of the most significant tell-tale signs of cancer is the circumvention of apoptosis by the cells. This is achieved by: disheveling the signaling cascade, inducing P 53 mutations, curtailing the expression of caspase, heightening the expression of IAPs and forcing the BCl2 family into a disarray [2]. Down regulation of death receptors and death signals is linked to cancer.
Structural aberrations in FADD and trail DR5 results in the impaired relay of signals. The death ligands may also associate with a condeath receptor resulting in the failure of construction of the DISC.
P53 which normally is a preserver of genomic stability undergoes oncogenic activating leading to exorbitant proliferation of cancer cells. The initiator caspases (2,8,5,6) and effector caspases (3 and 7) are suppressed, and their functions are hindered. Inhibitors of apoptosis proteins mediate the apoptotic pathways by bringing down the caspase levels. They also regulate NF-kappaB, consequently bringing down apoptosis. The fine balance maintained between the bcl2 family [between pro and anti-apoptotic proteins] also ensures optimal functioning of the apoptotic cascade. The pathways outlined are not solely responsible for overriding apoptosis but are certainly the key players in cancer related apoptosis [3]. were upgraded to possess Cys residues. The well-known toxicity of MMAE was the driving force behind PEG addition. The induced modification in the TRAIL structure aided in the conjugation of methoxy PEG which was established to be more efficacious [9]. Use of a "Leucine Zipper "has been explored which brings stability to the TRAIL trimers, hence pushing the cells towards apoptosis. The leucine zipper comprises the replacements in 2 positions (a, d) and

Targeting Trail
was subsequently fixed with TRAIL, which sustains the formation of TRAIL trimers. Algorithms like AGADIRI and bZIP have been utilized to select the zipper content [10]. Another strategy utilizes Elastin-like polypeptides to enhance the potency of antitumor activity. These are primarily purified from human tropo-elastin and are depicted as having VPGXG repeats. It has self -assembling properties and is easy to extract and hence is a promising lead. In addition, they are also easily degraded and non -toxic. The RGD -TRAIL add-ons make the molecule heat stable. The molecules begin to clump at 40 C. They have the added benefit of being able to self-aggregate and make up a nanoparticle. All of these tactics are anti-cancer therapies and exploitation of these could lead to better susceptibility of cancerous cells to treatment procedures [11].

Targeting Caspase Mediated Pathway
Apoptosis is engineered by various biomolecules. Caspases

Targeting Bax-Bak Pathway
Another principal mechanism in apoptosis is the Bax-Bak

Targeting Akt Pathway
Huachansu is a well-known traditional medicine and is also known as Chansu. Chansu is derived from the parotid gland of Bufo gargarizans. Huachansu has many components like bufadienolides, nucleosides, and alkaloids which gives them the property of detoxification and also the functionality of an analgesic.
This molecule has been used previously to cure many diseases,

Targeting p53
Oridonin, an active deteprene compound is believed to have anti-cancer, anti-inflammatory and anti-bacterial effects. Oridonin

Targeting Sirt
Curcumin, a well-known herb, is derived from the Curcuma longa and is also referred to as turmeric and is very well known for its activity in preventing and treating various cancers. It is also

Other Encouraging Molecules
Myostatin belonging to TGF-β superfamily is known for muscle wasting during cachexia in cancers and hence it plays a very crucial role in the progression of cancer. The Mstn-KO induces phosphatidylserine externalization in the outer leaflet of the bi-layer membrane where the PI in the Mstn-KO indicates apoptosis through mitochondrial pathway [28]. Treatment with phenolic acids can induce apoptosis in cancer cells in both G2/M and S phases. Its presence can also enhance the levels of some proapoptotic proteins such as BAK and FAS leading to the initiation of death signals resulting in apoptosis. It also has intrinsic free radical scavenging nature as well as antioxidant activity [29]. A cytotoxic herb, Raddeanin A, exposure to which results in reduction of wee 1 signaling and in the down-play of caspase activity, contributing to its pro -apoptotic action [30]. DYRKIA is suppressed by SiRNAS and which results in the weakening of the metastatic capabilities of MNSCC. It is noted that the exposure to an inhibitor of DYRKIA caused slow-down in tumor growth [31]. Anti -EpCAM [SCFr] -

MAP acts by tubulin stabilization, it is classified as an ADC or an
immunotoxin. Anti -EpCAM serves as a high potential treatment strategy owing to its specificity and binding affinity [32]. The epigenetically modified Naa4O acts on histones H4 and HZA, it is a variant of the NAT enzymes which aid in diethyl -group transfers.
Though the role of Naa40 is contradictory in lung cancer [where it promotes growth]; it has been shown to delay the proliferation of breast and colon cancers. This has been associated with activation of p53 -dependent apoptotic pathways [33]. Acriflavine [HIF The lack of efficiency in existing treatment strategies for cancer is both widely known and accepted, warranting the need for further research. The development of targeted therapy has gained recognition and novel approaches have become the need-of-hour.
We emphasize on the need for further research on these leads so as to make them highly feasible and reduce their side-effects. We propose the use of such strategies in routine treatments to provide better patient care.