**3. Necessity for drug repurposing in cancer treatment and availability of attractive candidates**

Comparing cancer with other disease that takes much time to develop and working insidiously. Every cancer begins with few mutations that suppress tumor suppression gene and promoting oncogene that leads to abnormal cell proliferation, escape of apoptosis, immune evasion, inflammation, defects in DNA damage repair mechanism, Warburg effects, angiogenesis and lack of differentiation of cell with most of the cells remain immature. As there is progress happen the picture of tumor microenvironment become more and more complicated. At this time tumor is no more homogenous but packed with heterogeneous cells and changing itself to more resistance form. The cancer might be supported by systemic condition of the body or in the other words internal anti-cancer mechanism become compromised to eradicate the tumor. The tumor microenvironment begins to secret many immunosuppressive cytokines and inflammatory mediators that sustain the tumor growth and save this corrupted cellular structure against honest immune system that work in the form of vigilance. After dominate at local region, tumor intrude to the other favorable region. Later on, metastasis start based on seed and soil theory of Stephan Paget, where cancer cells work as "seeds" and the specific organ microenvironments work as "soil." The success interaction between these two entities determines the development of a secondary tumor [11].

After get metastasis, the most of the patients give response to first line treatment not more than 50% for various cancers. At advance stages of cancer, majority of patients will develop anti-cancer resistance due to drastic abnormal genetic, epigenetic changes and surviving of cancer stem cells that not killed even after the death of tumor cells [12, 13]. So, it becomes important to repurpose drugs that able to act at multiple targets in tumors in patient that display genetic heterogeneity.


**125**

**Figure 3.**

*Hall marks of cancer.*

*Drug Repurposing in Oncotherapeutics DOI: http://dx.doi.org/10.5772/intechopen.92302*

Artemisinins Induce formation of

Doxycycline Protein synthesis in

*Repurposed drug for the cancer treatment.*

bacteria

Chlorpromazine

[19]

**Table 1.**

**Drug First approved target Approved in** 

Dopamine receptor antagonist

reactive oxygen species (ROS) within the infected red blood cells (RBC)

**3.1 Various anti-cancer targets that can be used for repurposing of drug**

repurposing in oncotherapeutics (**Figure 3**).

Based on global statistics, more than 20 million individuals will be detected with cancer in 2025. Certain cancer like breast cancer, colorectal, prostate is mostly remaining incurable in advanced stages with existing treatment and that leads to increase in number of cases. Thus, addressing these present and future challenges requires more effective cancer drugs [29]. Traditional anti-cancer therapy like Chemotherapy and radiation have dangerous side effects that range from bone marrow suppression, oral mucositis, arising of secondary cancer to vomiting, diarrhea and organ specific toxicity that drastically decrease the quality life and overall survival of cancer patients [30]. From this point of view, drug repositioning option is promising strategy to identify non-cancer drugs like aspirin and chlorpromazine which have anti-tumor activity with less side effects comparable to traditional anti-cancer drugs. Traditionally limited targets were identified for anti-cancer drugs that involve cell cycle inhibitors, anti-metabolites, anti-angiogenesis, growth factor inhibitors, pro-apoptotic. But today many new targets identified that work in more specific way and reduce dangerous side effects of anti-cancers. Some novel drug target mentioned in following diagram that might be work well for future drug

**disease**

In psychosis, bipolar disorder, schizophrenia

Anti-malarial [25]

**Repurposed in cancer (preclinical/clinical)**

[24]

effects [26]

Antibiotics Down regulation of MMP-2 and

Increase in p21 [23], p51 expression

Anti-proliferative, pro-apoptotic

MMP-9 expression in leukemia [27] and colorectal cancer cells [28]

The following table (**Table 1**) consists of brief reviews of available good drug candidates for drug repurposing and some of that already approved.


**Table 1.**

*Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications*

candidates for drug repurposing and some of that already approved.

**disease**

Nausea, vomiting of pregnant woman (banned

now)

Type-II diabetes mellitus

suppressant

breast cancer

aggregation in cardiovascular disease

reduce heart rate

diseases

COX-1 Prevent Platelets

**Repurposed in cancer (preclinical/clinical)**

TNF-α

Multiple myeloma by targeting

Mitochondrial respiration, reducing insulin and insulin-like growth factor levels, inhibits mTOR and activate p53, AMPK pathway

In Pancreatic neuroendocrine by targeting mTOR signaling pathway

For HER2-positive metastatic

Prostaglandin E2 (PGE2) decreased in colon cancer [18], inhibition of platelets to suppress NK cellmediated lysis of cancer cells [19]

Reduced 57% risk of metastasis in Breast cancer by blocking cyclic AMP (cAMP), focal adhesion

Rise in intracellular Na + and Ca2+ in human prostate adenocarcinoma cells, lead to activation of calcineurin and transcriptional upregulation of Fas ligand cause apoptosis. Also, suppression nuclear factor-kappa B and inhibition of DNA topoisomerase II are well documented.

gastric cancer

kinase (FAK)

**Drug First approved target Approved in** 

medullary control centers (the vomiting center and the chemoreceptive trigger zone) or affect the peripheral receptors

monophosphate activated protein kinase (AMPK) signaling pathway

Everolimus [16] mTOR Immuno-

Trastuzumab [17] HER2 HER2-positive

Propranolol [20] β-receptor blocker Cardiovascular

Digoxin [21, 22] Na + -K + -ATPase Heart failure, to

Thalidomide [14] Might affect the

Metformin [15] Activate the adenosine

Aspirin (low dose; 50–100 mg daily)

Warburg effects, angiogenesis and lack of differentiation of cell with most of the cells remain immature. As there is progress happen the picture of tumor microenvironment become more and more complicated. At this time tumor is no more homogenous but packed with heterogeneous cells and changing itself to more resistance form. The cancer might be supported by systemic condition of the body or in the other words internal anti-cancer mechanism become compromised to eradicate the tumor. The tumor microenvironment begins to secret many immunosuppressive cytokines and inflammatory mediators that sustain the tumor growth and save this corrupted cellular structure against honest immune system that work in the form of vigilance. After dominate at local region, tumor intrude to the other favorable region. Later on, metastasis start based on seed and soil theory of Stephan Paget, where cancer cells work as "seeds" and the specific organ microenvironments work as "soil." The success interaction between these two entities determines the development of a secondary tumor [11]. After get metastasis, the most of the patients give response to first line treatment not more than 50% for various cancers. At advance stages of cancer, majority of patients will develop anti-cancer resistance due to drastic abnormal genetic, epigenetic changes and surviving of cancer stem cells that not killed even after the death of tumor cells [12, 13]. So, it becomes important to repurpose drugs that able to act at multiple targets in tumors in patient that display genetic heterogeneity. The following table (**Table 1**) consists of brief reviews of available good drug

**124**

*Repurposed drug for the cancer treatment.*
