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 Table of Contents  
REVIEW ARTICLE
Year : 2013  |  Volume : 2  |  Issue : 2  |  Page : 69-74

The potential therapeutic targets for cervical cancer


1 Department of Pharmaceutics, JSS College of Pharmacy, Rocklands, Udhagamandalam, Tamil Nadu, India
2 Department of Pharmacology, JSS College of Pharmacy, Rocklands, Udhagamandalam, Tamil Nadu, India
3 Department of Pharmacognosy and Phytopharmacy, JSS College of Pharmacy, Rocklands, Udhagamandalam, Tamil Nadu, India

Date of Web Publication26-Jul-2013

Correspondence Address:
K Gowthamarajan
Department of Pharmaceutics, JSS College of Pharmacy (A Constituent College of JSS University, Mysore), Post Box No. 20, Rocklands, Udhagamandalam, Tamil Nadu
India
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Source of Support: CSIR, New Delhi, Conflict of Interest: None


DOI: 10.4103/2278-344X.115679

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  Abstract 

In case of invasive cervical carcinoma several molecular events were reported and these molecular events resulting in multiple genetic abnormalities. In order to control these tumors multiple molecular therapeutic targets are needed with different molecular mechanisms. Unfortunately, these molecular targets were in early stages of development. Because of less degree of success of conventional therapeutics for late stages of cervical cancer and lowering of prognosis of patients there is an increase in interest for the development of potential therapeutic targets for cervical cancer. This review article emphasizes the current molecular targeted agents; with special attention to estrogen receptors for human papilloma virus infected cervical cancer.

Keywords:  Cervical cancer, human papilloma virus, molecular targets, therapeutics


How to cite this article:
Dwarampudi L P, Gowthamarajan K, Shanmugam R, Madhuri K, Nilani P, Satish Kumar M N. The potential therapeutic targets for cervical cancer. Int J Health Allied Sci 2013;2:69-74

How to cite this URL:
Dwarampudi L P, Gowthamarajan K, Shanmugam R, Madhuri K, Nilani P, Satish Kumar M N. The potential therapeutic targets for cervical cancer. Int J Health Allied Sci [serial online] 2013 [cited 2020 Jun 2];2:69-74. Available from: http://www.ijhas.in/text.asp?2013/2/2/69/115679


  Introduction Top


Due to shortage of potent molecular targets for late stages of cervical cancer and less prognosis of patients, [1] there is a scope for the development of potent therapeutics as well as molecular targets for cervical cancer. During the last decades, several molecular targets for cervical cancer have been investigated. In our current review article, we focused on potential therapeutic targets for cervical cancer.


  Targetted Therapies Top


Various potential therapeutic targets for cervical cancer were listed in [Table 1], [Figure 1] and cervical cancer progression was given in [Figure 2].
Table 1: Recent molecular targets for cervical cancer

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Figure 1: Molecular targets and various receptors involved in cervical cancer. EGF is epidermal growth factor (EFGR), epidermal growth factor receptor is EFGR receptor hepatocyte growth factor (HGF) is HGF, Insulin like growth factor (IGF‑1) is type I insulin‑like growth factor, IGFR is IGF receptor, VEGF is vascular endothelial growth factor, VEGFR is vascular endothelial growth factor receptor, Hypoxia‑inducible factors‑1 is the subunit of the hypoxia‑inducible factor 1, MAPK is mitogen‑activated protein kinase, mTOR is mammalian target of rapamycin, p53 is protein 53, PI3K is phosphoinositide 3'‑kinase, pRb is retinoblastoma protein, E6 is human papilloma virus (HPV) early protein 6, E7 is HPV early protein 7

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Figure 2: Cervical cancer progression via human papilloma virus infection in cervical epithelium

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Receptor kinases

Anti-EFGR therapies

The family of epidermal growth factor (EFGR) receptor consist of four receptors, EFGR receptors also known as human epidermal growth factor (HER) 1, HER-2/neu, HER-3, HER-4. These receptors have three domains extracellular, transmembrane and intracellular and were located in cell surface. The specific ligand activation of these receptors leads to the activation of tyrosine kinase resulting in cell proliferation. [2] In recurrent cervical cancer, EFGR receptors are over expressed and this condition leads to the advanced stage of the disease. [3],[4],[5] Research proven that anti EFGR therapies might be more effective in patients with advanced stages of cervical carcinoma where patients were already treated with multiple dosage regimens. [6] So, it is one of the interesting therapeutic targets for cervical cancer.

Hepatocyte growth factor (HGF/C)-met inhibitors

The HGF is the ligand of c-met, a membrane spanning receptor involved in various biological activities including motility, proliferation, survival, invasion, and morphogenesis. The axis of HGF/c-met involved in a variety of epithelial, haematological and mesenchymal malignancies. There was a significant correlation between the axis of HGF/c-met with oncogenic human papilloma virus (HPV's in severity of intraepithelial leisions. The over expression of HGF/c-met complex in cervical carcinoma conditions indicates that HGF/c-met inhibitors may play an important role in cervical cancer. [7],[8]

Insulin like growth factor (IGF/1R) targeting agents

The IGF receptor pathway comprises ligands such as IGF-1 (IGF-1R), IGF-2 and Insulin receptors and IGF/1R responsible for the fetal development and growth of organ. IGF/1R signal Interruption resulted in cancer cell growth inhibition and motility in vitro as well as in vivo. [9] Non-linear activation of IGF/1R pathway was associated malignant neoplasm s such as multiple myeloma, prostate cancer, non-small cell lung cancer and renal cell cancer. Research demonstrates that cervical cancer associated with HPV infection IGF receptors over expressed. It indicates that it is an interesting target in cervical cancer treatment. [10]

Intracellular signaling kinases

Phosphatidylinositol 3 phosphoinositide 3' kinase (PI3K)/serine-threonine kinase (AKT)/mammalian target of rapamycin (mTOR)

The PI3-kinase ([PI3K]/AKT/mTOR) pathway acts as a cell sensor for nutrients and growth factors. [11] mTOR also known as mammalian target of raphamicin inhibition. The PI3K/AKT/mTOR pathway is a good target for molecular therapies. This pathway kinases are over activated in many varieties of solid tumors. [12] PI3K/AKT/mTOR pathway activation was associated with cervical cancer chemo resistance and worse prognosis.

Ras/Raf/Mitogen-activated protein kinase pathway (MAPK)

In humans H RAS, K RAS and N RAS genes were located in chromosomes 11, 12 and 1 and mutations among them play an important role in carcinogenesis process. RAS consist of GTPase protein, which transmits signals from oncogenes to RAF and then to MAPK. [13] Mitogen activated protein kinase pathway is the connector between extracellular and intracellular stimuli responsible for malignant transformation. [14] The interferences in pathway leads to cervical carcinoma.

Angiogenesis

Anti-vascular endothelial growth factor therapies

The vascular endothelial growth factor (VFGF) and vascular endothelial growth factor receptors (VFGFR) are the factors regulating angiogenesis. [15] Angiogenesis is responsible for progression of HPV infected cervical cancer. [16] Over expression of VEGF results in worse progression of cervical cancer. [17] Among several pro-angiogenic factors studied for cervical cancer, the VEGF was consistently over expressed. Studies on transgenic mice models and human cervical tissue expressing E6 and E7oncogenes provided supporting evidence for the same. [18] Therefore, VEGF signaling may be an attractive target for HPV infected cervical cancer.

Hypoxia-inducible factors (HIF) factors

HIF-1 and HIF-2 are important mediators responsible for tumor angiogenesis. [19] Under normal oxygen conditions HIF-1 subunit was rapidly degraded under normal oxygen atmosphere by ubiquitin proteasome system. The hypoxic tumor micro environment was responsible accumulation of HIF-1, resulting in loss of tumor suppressor genes such as VHL (Von Hippel-Lindau tumor suppressor), p53 and PTEN (Phosphatase and Tensin Homolog), which lead to tumor progression. [20] Over expression of HIF-1 as a result of HPV genomic integration, in premalignant lesions results in cervical cancer. Both E6 and E7 oncogenes were responsible for HIF-1 production, suggesting that it may be a promising target in HPV infected cervical cancer. [21],[22]

Cytotoxics

Natural or semi synthetic cytotoxic agents play an important role in achieving targetable molecular changes in cancer either alone or in combination with other targets. The toxicity associated with classical cytotoxics resulted in development of novel cytotoxic drugs. People suffering from cancer receive cytotoxics either as single or in combination with other targets. The basic principle for development of novel cytotoxics was better pharmacodynamic and pharmacokinetic profiles. There are a lot of newer cytotoxic agents under evaluation for cervical cancer therapy. [23]

HPV directed therapies

Literature support strongly indicates that E6/E7 oncogenes are responsible for cervical cancer. But targeting E6/E7 oncogenes is not only effective therapy for HPV directed cervical cancer Potential therapeutic targets and small molecules such as antivirals, Small interfering RNA, antisense oligodeoxynucleotides or ribosomes block oncogenes and responsible for anticancer potential. [24],[25],[26],[27] The ability of small molecules to interfere E6 ability via p53 degradation resulted in finding specific therapeutic targets for HPV infected cervical cancer. [28]

Poly (adenosine diphosphate [ADP]-ribose) polymerases (PARP) inhibitors

PARP play an important role in base excision repair pathway. PARP Inhibitors causes mutations in tumors which resulted in cell death. PARP Inhibitors already became successful in case of breast and ovarian cancer. Preclinical data suggests PARP Inhibitors had potential effects in cervical cancer that play may an important role in cervical cancer therapy. Clinical trials in relation to PARP Inhibitors is in progress with respect to gynecological cancers. [29],[30]

Epigenetics

Epigenetic therapy includes the use of DNA methyl transferase and histone deacetylase inhibitors alone or in combination. The epigenetic drugs interact with HPV E6 and E7 oncoproteins resulted in cell transformation and tumor suppressor genes transcriptional inactivation. Targetable epigenetic alterations were reported in cervical cancer. The epigenetic drugs were under phase III clinical trials in cervical cancer. The literature suggests that epigenetics may play an important role in cervical cancer treatment. [31]

Immunotherapeutic agents

Immunotherapeutic agents act by an immune response mediated therapeutic activity against cervical cancer, which is at early development stages of clinical trials. Mapatumumab an immunotherapeutic agent human agonistic monoclonal antibody aimed at tumor necrosis factor. Bryostatin-1 targets toll like receptors 4 and interleukin-12 by systemic administration. [32],[33],[34] Due to less therapeutic effects associated with prophylactic vaccines, HPV specific therapeutic vaccines have an impact on cervical cancer incidence, since they work on E6 and E7 oncogenes as they are expressed in cancer lesions.

Estrogen receptor (ER) blockers

Estrogen, along with receptors ERα and ERβ involved in various physiological processes including female reproductive track, breast, colon, brain, bone, cardiovascular, and immune systems. Estrogen is involved in various cancers such as breast, endometrium, and cervix. [35] Even though, uterine cervix is highly responsive to estrogen its impact on cervical cancer is understood poorly. Recent studies in HPV transgenic mouse models revealed that Estrogen and its receptors along with HPV promote cervical cancer. [36] Clinical trials were under investigation. Hence, extensive research is needed in this area because the responsiveness of selective estrogen receptor modulators (SERM's) because human cervix is highly responsive to estrogen and potentiality of SERM's having been proven from preclinical trials.

Biological agents

For locally advanced cervical cancer, the gynecologic and oncologic group in Europe in early 1990's used the combination of hydroxy urea and radiation, but a recent review while evaluating randomized published control trails excluded this drug from current chemotherapy options. [37] for the treatment of cervical cancer 5-fluorauracil alone had no major role. [38] in 1969 with the discovery of cisplatin the tremendous progress has been reported in various cancers including cervical cancer of advanced stage, since it is widely recommended therapy now-a-days. However these results should be justifiable with clinical trials with a large group of people to understand the side effects associated with cisplatin. Another platinum based drug carboplatin is recommended for cervical cancer, which possesses a high degree of chemical stability than cisplatin and almost equivalent activity, but more research yet to be focused on this molecule.

In Japan, another platinum based drug nedaplatin shown a good preclinical activity and lack of cisplatin associated nephrotoxicity. [39] From 1960's cytotoxin mitomycin C, has been utilized for a variety of cancers. Mitomycin C in combination with 5-fluoro uracil utilized for chemo radiation for locally advanced cervical cancer. Although mitomycin C is a good radiosensitizer the bowel toxicity is the main side effect associated with this drug. [40] An anthracycline analogue, epirubicin alone had activity against advanced or recurrent cervical cancer. Study reports suggested that the adjuvant component may be responsible for the activity of epirubicin. [41]

The campothecin such as topotecan reported limited clinical trials as radiosensitizers, but associated with hematological toxicity. The stage IV clinical trials of 2 mg/m 2 topotecan in combination with 40 mg/m 2 standard cisplatin displayed 92% recovery rate and one patient remained disease free among the 12 patients tested but resulted in higher neutropenia in which this combination deserves further clinical trials. [42] Another campothecin irinotecan is not a promising molecule for cervical cancer. A semi synthetic vinca alkaloid vinorelbine administration alone resulted in hematological toxicity and in combination with paclitaxel least tolerable. [43] The preclinical data on microtubule stabilizer paclitaxel suggested the limited activity in cervical cancer alone. However, potent in combination with either cisplatin or carboplatin for cervical cancer but still there is a controversy in establishing safe dosage regimen. A fluoropyrimidine carbamate, capecitabine based chemo radiotherapy is a well-tolerable option and its efficacy in early stages needs further evaluation. [44] In patients with locally advanced cervical cancer, a deoxycytidine analog, gemcitabine along with cisplatin, external radiation and brachytherapy improved patient outcome with acceptable toxicity. [45] The interferon's and retinoids combination was not successful treatment for cervical cancer.


  Conclusion Top


Being a preventable disease cervical cancer is spreading for a large number of women world-wide with high mortality rate. HPV vaccines prevent spreading of cervical cancer in non-infected people. Moreover, Vaccines are effective only against certain strains of HPV. The evidences from cytotoxics recommended them as best drugs for cervical cancer, but more focus should be there on their side-effects. The drug cisplatin positioned as standard drug of choice because of its efficacy and good toxicity profile against cervical cancer treatment. The old drugs such as mitomycin, fluorouracil had very limited role in this cancer. In phase I and II clinical trials, the cytotoxics such as capecitabine, gemcitabine, paclitaxel, topotecan, vinorelbine demonstrated potent activity alone or in combination with cisplatin. Phase III clinical trials of gemcitabine combined with cisplatin demonstrated superiority in survival rate when compared with cisplatin alone. Stage IV B recurrent or persistent cervical cancer cisplatin combination with gemcitabine, paclitaxel, topotecan, and vinorelbine had produced equivalent best survival rate but different toxicity profiles. However, the long-term toxicity of each agent should be evaluated individually because each molecule had a different set of toxicity events. The bevacizumab produced unique activity as an angiogenesis inhibitor is being evaluated alone and in combination with cisplatin. Finally, cisplatin is the superior drug of choice. Several molecular and therapeutic targets are available for cervical cancer, but all are almost in early stages of development. The results of various biological agents being tested are awaited. More advanced therapies are needed for patients suffering from recurrent cervical cancer in clinical perspective. Hence, it is very essential to broaden research in the area of targeting cervical cancer via molecular targets. In developing countries like India, the burden of cervical cancer is increasing; hence such kind of studies lead to the development of new effective therapies for HPV infected cervical cancer.


  Acknowledgments Top


Authors wish to thank Council of Scientific and Industrial Research (CSIR), New Delhi for providing Senior Research Fellowship to Miss L Priyanka Dwarampudi, JSS University, Mysore and The Principal, JSS college of Pharmacy, Udhagamandalam for providing necessary facilities.

 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1]


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