Cancer treatment

Cancer treatment


In the present scenario, cancer treatment is big question for the physicians and researchers. The ratio of cancer patients are increases day by day. There are no vaccines or medicines available which can cure cancer and very few medicines are available which cure the cancer but they have more side effects. So it is serious problem for the humans. This review article represents the targeting strategies for development of novel anti-cancer agents at molecular level. By developing various inhibitors cancer can be cure. The targets such as inhibitors of cdk, HSPs, VEGF, FGF and other targets such as mitochondrial targets, small RNA molecules, and inhibition of Raf-MAP pathway leads to cell death in cancer and finally arrest the cell growth. Researchers were successful to develop some molecules which stops the cell growth, but still more research work is need to combat against cancer. This review describes the main molecular targets and gives hope to treat cancer.


Cancer is characterized by uncontrolled cell proliferation, growth arrest and apoptosis. Genetics of cancer mainly involves the activation of proto-oncogens to oncogens and inactivation of tumour suppressor gene due to altered gene expression which are responsible for apoptosis, control cell division, and differentiation. The proto-oncogens such as IGF, c-sis, c-ras, abl, c-src, c-myc, c-jun, c-erbB etc. are responsible for uncontrolled cell-proliferation. The tumour-expression genes such as p53, rb1, cdk inhibitors etc. are responsible for decrease apoptosis (1). So, this changes in proto-oncogens and tumour suppressor genes leads development of primary tumour and further secondary tumour (2).The figure 1 shows the development of anti-tumour agents at molecular level. The targeting strategies such as development of inhibitors of cdk and HSPs, targeting VEGF and FGF in angiogenesis, development of anti-sense, si-RNA and dsRNA as small RNA molecules, by leading mitochondrial dysfunction and finally by stopping Raf-MAP kinase pathway, tumour growth can be stopped.

1. The cell cycle - A targeting strategy

Cell cycle is an event through which proliferating cell replicates its entire component and converted to its two identical daughter cell. The phases of cell cycle are

M phase - mitosis

S phase - DNA synthesis

G1 phase - gap between M and S phase

G2 phase - gap between S and M phase

The releases of growth factors from a cell are bind to receptors on the cell membrane which results in transfer of signal through the membrane to cytoplasmic proteins, and further release of transcription factors within the nucleus. This succession of events pushes the cell through the cell cycle (3, 5).

The cell division requires two main events: S phase (DNA replication) and M phase (mitosis). G1 phase is also called pre-DNA synthesis phase where cells start to rise. During this phase the concentration of cyclin D increases and the cyclin D/cdk complex phosphorylates and activates the necessary proteins (6). According to I. Foster, “In the early phase of G1, mitogens signal are received by the cell which results in the Ras dependent kinase cascade. Activation of transcription genes is done by phosphorylation of cycline D/cdk complex with retinoblastoma (Rb) protein, which releases the bound transcription factor (E2F).” This activation is required for the next phase-DNA synthesis-namely cyclins E and A, DNA polymerase and so on. cyclin E/cdk complex is essential for conversion of G1 to S phase (3).

The proteins/enzymes involve in S-phase i.e., DNA synthesis are activated by phosphorylating Cyclin E/cdk and cyclin A/cdk complex. In G2 phase, the numbers of chromosomes are double and Cyclin A/cdk and cyclin B/cdk complexes become active which allows entry in to M phase (4, 7). By developing inhibitors of cdk, phosphorylation can be stopped and finally inhibition of cdk expression leads to cell arrest (figure 2).

G2 phase is also called post- DNA synthesis phase where it give rise to pair of chromosomes in nucleus and then this chromosomes give rise to two daughter cells in M phase. To conclude, the development of cdk inhibitors stops the DNA synthesis and thus prevents the mitosis phase and further cell division. So, the growth of tumours can be stopped.

2. Role of p53 and its target

The p53 has makeable biological effects involving cell-cycle arrest, DNA replication and repair, proliferation, apoptosis, angiogenesis inhibition, and cellular stress response (8, 9, 20). The p53 protein can be divided into several domains, such as N-terminal transactivation domain which contains the Mdm2- binding site, the core domain that possesses particular DNA-binding activity, and the C-terminus of the protein that is involved in regulation of the sequence-specific DNA-binding function which contains the oligomerization domain. Recently, a proline-rich domain has been identified between the transactivation and DNAbinding regions and it is important for interaction with SH3-containing domain proteins (10, 12, 13,).

p53 activity is controlled mostly by ubiquitin ligase and Mdm2 (mouse double minute 2) at the protein level, which targets p53 to proteasomal degradation and inhibits its transcriptional activity. MDM2 protein has a short half-life. A recent study has suggested that C-terminus acetylation is mandatory for p53 activity (11, 14, 15, 20). Michael H.G. Kubbutat reported that “Inhibition of p53-Mdm2 interaction results in accumulation of transcriptionally active p53, demonstrating that in undamaged cells Mdm2 is essential for keeping p53 levels low.” Lead molecules can be designed that can bind MDM2 and activate the wt-p53 response. Current research is progress in drug-development portfolio into ubiquitination- inhibitors, nuclear export inhibitors and proteosome inhibitors (figure 3) (16-19).

To conclude, the development of ubiquitin ligase inhibitors and proteasome inhibitors increases the level of p53 which has potential effect in cell cycle arrest, thus cancer can be treated.

3. Heat shock protein (HSPs) and Apoptosis

These proteins are also known as stress-response proteins and found in both prokaryotes and eukaryote (27). They induced by various environmental and pathophysiological stresses and have a dual function depending on their intracellular or extracellular location (21-23). According to their molecular size, HSPs have been classified into subfamilies like HSP10, HSP27, HSP40, HSP60, HSP70, HSP90, HSP110 and the small HSPs. The main focuses of HSPs are on HSP70, HSP90, HSP40 and HSP27 which are highly induced by stresses such as heat, oxidative stress, or anticancer drugs (25, 27). M. Santarosa et al reported that HSP27 is expressed in a significantly higher percentage of renal cancer cells than normal renal cells.

HSPs are the inhibitors of programmed cell death (PCD) and senescence (24-28). At the postmitochondrial level, HSP27 binds to cytochrome and increases level of HSP 27 that inhibits the activation of caspase cascade by caspase 9. HSP70 and HSP90 bind to Apaf1 (apoptotic-activating protease factor-1) in most cases resulting in the inhibition of apoptosome formation and thereby prevention of caspase activation and apoptosis (Figure 4) (26,27,30,31). Geldanamycin analogs are first specific HSP-90 inhibitor were discovered by Whitesell et al (33).

RIP (receptor interacting protein) is adapted to the receptor and promotes the activation of NF-KB by the ligation of TNFR. HSP90 stabilize the receptor interacting protein (RIP). HSP90 interacts with RIP1 kinase and AKT and allows promotion of NF-KB mediated inhibition of apoptosis (30). HSP70 also interact with AKT and allows promotion of NF-KB mediated inhibition of apoptosis (29). The Bcl-2 family is also targeted and the antisense compound named oblimerson is under phase III trial (2). In conclusion, the development of inhibitors of HSP27, HSP70 and HSP90 switches the activation of apoptosis and thus promoting the cell death in cancer.

4. Angiogenesisand cancer

Angiogenesis is the process of new vascularisation by which growing tumours establish a blood supply (33). Tumour induces blood vessel growth by secreting various growth factors such as VEGF (Vascular Endothelial Growth Factor) and bFGF (Basic fibroblast growth factor). VEGF and bFGF induce capillary growth into the tumour, which supply required nutrients and allow for tumour expansion (34-36).

VEGF has three receptors. VEGFR-1 and VEGFR-2 are considered to control angiogenesis, while VEGFR-3 is considered to control lymphangiogenesis (40). VEGF is a major contributor to angiogenesis which increases the number of capillaries in a given network. The presence of this growth factor proliferates and migrate plated endothelial cells, eventually forming tube structures resembling capillaries. VEGF is responsible for signalling cascade in endothelial cells (38). Binding to VEGF receptor-2 (VEGFR-2) starts a tyrosine kinase signalling cascade that stimulates the production of factors that variously stimulate vessel permeability, proliferation/survival (FGFs), migration and finally differentiation into mature blood vessels (34,39). So, by inhibiting VEGF, affinity of VEGF receptor-2 can be reduces by which tyrosine kinase signalling cascade have been deactivated and stops the vessels formation, hence cell proliferation and differentiation can reduce in cancerous cells (38).

FGFs (Fibroblast growth factors) are main key in the processes of proliferation and differentiation of wide variety of cells and tissues (42). FGF1 and FGF2 act through high affinity receptors identified as tyrosine kinase receptors (FGF-R1-R4) (41, 43). Thus they promote angiogenesis. So, by developing inhibitors of FGFs and tyrosine kinase, cell proliferation and differentiation can reduce in cancerous cells.

5. Small mitochondria-targeting molecules as anti-cancer agents

The mitochondrial structure and functions of normal cells and cancer cells is different which may provide a biological basis to preferentially target cancer cells. Alterations in mitochondrial function of cancer cell results in cell death. The increase of mitochondrial transmembrane potential in cancer cells may provide the apoptotic cell death process or preferentially disturb cancer cell metabolism (44-48). Dequalinium and F16 are the agents which altered the transmembrane potential of mitochondria in cancer cells and these agents are under pre-clinical testing (49-52).

The level of Bcl-2 is overexpressed in cancer cell which block the apoptosis. By targeting Bcl-2, mitochondrial permeability pore get open which releases the apoptotic factors and finally results in apoptic cell death (53). Gossypol is a Bcl-2 inhibitors and under Phase III clinical trial (54-55).

Glycolytic activity is increases in cancer cells with mitochondrial dysfunction, which provides ATP and other metabolic intermediates for cancer cells to survive and proliferate. Activity of enzymes is altered in glycolysis and the tricarboxylic acid (TCA) cycle has been observed in cancer cells (56). Therefore, researchers have developed various inhibitors of enzymes such as Hexokinase (HXK), pyruvate dehydrogenase kinase and lactate dehydrogenase (LDH) which is shown in table.

6. RNA molecules as anti-cancer agents

Double-stranded RNA is formed by hybridization of antisense RNA with its target mRNA and affect the processing of the mRNA, its stability, its nucleocytoplasmic transport and its translation. Generally, Cancer is results from deregulation of more than one protein, so the silencing the expression of most dominant protein leads to cancer cell death. By developing antisense RNA, protein expression can be reduced to mRNA that codes for cancer associated protein (57). Antisense RNA is also designed to inhibit IGF-IR gene expression and reduces the IGF-I-dependent proliferation and survival in human and rodent cancer cell lines (58,59).

Delivery of siRNA in to cancer cells is responsible for reducing expression of the EGFR (epidermal growth factor receptor) in cultured cells and decreases proliferation and apoptosis (60). Double-stranded RNA can be introduced into mammalian cells, where it activates various cellular pathways, especially activation of PKR which lead to cell death (figure 5) (57).

Figure 5: RNA molecules such as anti-sense RNA, siRNA and dsRNA as a cancer targeting molecules.

So the development of small RNA molecules such as anti-sense RNA, siRNA and dsRNA provides the anti-proliferative activity and cell death and thus cancer can be cure.

7. Targeting the RAF-MAK pathway in cancer therapy

Binding of growth factor to its RTK or cytokine receptor activate Ras-GTP complex. This Ras-GTP activation leads interaction of the Raf N-terminal regulatory domain which results in dephosphorylation and finally leads to activation of Raf kinase activity. This active Raf kinase switches the activation of MAP kinase (61). MAP Kinase regulates the activity of many transcription factors that controls early-response genes which are require for replication of DNA (31). So, by targeting MAP kinase and Raf kinase, transcription can be stopped and hence growth of cancerous cell can arrest (Figure 6).

Figure 6: Inhibition of RAF-MAP kinase pathway stops the transcription and cell growth.

Sorafenib is the first and only RAF kinase inhibitor that has received clinical approval by the Food and Drug Administration (FDA) and European Medicines Agency (EMEA). RAF265, XL281and PLX4032 are selective RAF kinase inhibitor that currently undergoing clinical evaluation (62-63). CI-1040 was the first selective MEK kinase inhibitor to reach clinical development, while PD0325901 is a second-generation MEK inhibitor which has improved pharmacologic and pharmaceutical properties compared to CI-1040 (64-67).

The table below shows the information about some drug molecules which act on specific target and are under clinical and pre-clinical evaluation.

Drug molecule

Molecular target

Phase of development

geldanamycine derivative (17-AAG)

HSP90 inhibitor

Pre-clinical testing


Bcl-2 inhibitor

Phase III

Gefitinib, ZD6474, sorafenib

tyrosine kinase inhibitor

Phase II / III


RAF inhibitor

Phase I

PD0325901, AZD6244, XL518, CI-1040 (PD184352)

MEK inhibitor

Phase I / II


proteasome inhibitor


VEGFR-1/2 tyrosine kinase inhibitor

Phase II

MKT-077, Rhodamine123

Altered mitochondria transmembrane potential

Phase I

Dequalinium, F16

mitochondria transmembrane potential

Pre-clinical testing

Betulinic acid, Honokiol

mitochondrial membrane permeability

Pre-clinical testing


pyruvate dehydrogenase kinase (PDK) inhibitor

Phase II


hexokinase II inhibitor

Phase I


lactate dehydrogenase (LDH) inhibitor

Pre-clinical testing


Hexokinase inhibitor

Pre-clinical testing


The cancer is mainly associated with growth arrest and apoptosis and cell proliferation. Development of cdk inhibitors is a great hope to stop DNA synthesis at S phase, and further prevent the conversion in to two daughter cells. High level of p53 plays important role in apoptosis which is found to be low in cancer cell due to ubiquitination and proteosome. So the development of ubiquitination and proteosome inhibitors leads high level of p53 which results in cell death in cancer. The other approach is development of HSPs (heat shock proteins) inhibitors. The presence of HSPs inhibits the caspase cascade pathway (cell death), so inhibition of HSPs activates this pathway and results in cell death in cancer cell. VEGF and bFGF provoke capillary growth into the tumour, which supply required nutrients and allow for tumour expansion. The development of inhibitors of VEGF and bFGF gives great hope for arresting capillary growth in tumour cell. Mitochondrial function has key role energy production and also supply to cancerous cell. Mitochondrial dysfunction can be done by changing transmembrane potential, by developing inhibitors of enzymes such as Hexokinase (HXK), pyruvate dehydrogenase kinase and lactate dehydrogenase (LDH) which involves in glycolysis and the tricarboxylic acid cycle. RNA plays key role in translation of protein. Development of small RNA molecules such as anti-sense RNA, siRNA and dsRNA provides the anti-proliferative activity and cell death in cancerous cell. Finally, RAF-MAK pathway which regulate the transcription factors require for cell growth. Inhibition of this pathway leads cell cycle arrest activity. In the recent time, researchers have developed some inhibitors that have good therapeutic effect in preclinical studies and very few drugs are available in market. So there is need for development of more active molecules and inhibitors that arrest the cancer cell growth.

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