Summya Rashid

Chemopreventive Effect of Bauhinia Purpurea Against Chemically Induced Hepatocarcinogenesis via Amelioration of Oxidative Damage, Cell Proliferation and Induction of Apoptosis in Wistar Rats.

Objectives: In the present study we have evaluated the chemopreventive efficacy of Bauhinia purpurea against Diethylnitrosamine (DEN) initiated and 2 Acetylaminofluorine (2-AAF) promoted hepatocarcinogenesis in Wistar rats. Materials and Methods: Efficacy of Bauhinia purpurea against 2-AAF-induced hepatotoxicity was evaluated in terms of biochemical estimation of antioxidant enzyme activities (reduced hepatic GSH, glutathione peroxidase, glutathione reductase, catalase, and quinone reductase), histopathological changes and expressions of early tumor markers viz., ornithine decarboxylase activity (ODC) and proliferating cell nuclear antigen (PCNA) and also expressions of p53, Bax, Bcl-2, and caspase-3 were evaluated. Results: Oral pretreatment with B. purpurea significantly decreased the levels of serum toxicity markers, elevated antioxidant defense enzyme activities, s uppressed the expression of ODC and PCNA and P53 along with the induction of apoptosis in the pretreatment groups. Tumor incidences are reduced by pretreatment of B. purpurea. Histopathological findings revealed that B. purpurea-pretreated groups showed marked recovery. Conclusion: The results support the protective effect of B. purpurea against chemically induced liver cancer and acts possibily by virtue of its antioxidant, antiproliferative, and apoptotic activities.

Major Mediators Linking Inflammation and Cancer

Inflammation has been considered and included as the seventh hallmark of cancer (Hanahan and Weinberg 2011). The link between inflammation and cancers was noticed some 150 years ago as Virchow denoted that cancers have a tendency to occur at chronic inflammatory sites, and this was known as early as 1863. However, evidence from epidemiological studies suggests that persistent inflammatory diseases are often connected with increased risk of cancers. The investigation aiming at the association between inflammation and cancers initially led to the determination whether the reactive nitrogen and oxygen species produced by inflammatory cells like leukocytes recruited to the inflammatory foci to kill infectious agents may also cause mutagenic injury, thereby resulting in the initiation of tumor.

Classification of Cancer

Tumors can be either benign or malignant. However benign tumors are usually slow-growing extensive masses that compress rather than invade surrounding tissue. Benign tumors are not cancerous, i.e., cells do not extend to other parts of the body. But malignant tumors are cancerous. Cells in these tumors invade nearby tissues and extend to other parts of the body, and when it spreads from one part of the body to another, it is termed as metastasis. Cancers are categorized in two ways depending upon the type of tissue in which cancer originates known as primary site or the position in the body where the cancer first develops. Malignant tumors are generally fast growing which invade surrounding tissue and colonize distant organs extensively. The capacity of tumor cells to separate from the original mass (the primary tumor) and spread to other organs sets up metastasis. There are hundreds of different cancers from histological point of view which are grouped into six major categories: n n nCarcinoma is any malignant cancer that originates from epithelial tissues lining the inner or outer surfaces of the body, generally arising from endodermal or ectodermal germ layers during embryogenesis. Carcinomas invade surrounding tissues and organs and may metastasize or spread to lymph nodes and other sites (Witkiewicz et al. 2011). Common malignancies like breast, colon, and lung cancer are categorized as carcinomas. n n nSarcoma is a malignancy that originates from altered cells of mesenchymal origin in bone, muscle, or connective tissue. Thus, malignant tumors found in cancellous bone, cartilage, fat, muscle, or connective tissues are termed as sarcomas. They occur rarely in humans (Baba and Câtoi 2007). n n nLeukemia is a neoplastic disease that usually begins in the bone marrow and results in the abnormal development of white blood cells and is generally classified into acute and chronic forms. Additionally it is classified depending upon the type of white blood cells affected by the disease (Isaacs 2009). n n nLymphoma is a kind of blood cell tumor of lymphocytes. It originates in the glands or nodes of the lymphatic system, a network of vessels, nodes, and organs that purify bodily fluids and develop infection fighting white blood cells or lymphocytes (Cupedo et al. 2011). n n nMyeloma arises in the plasma cells of bone marrow. Sometimes myeloma cells accumulate in one bone and form a single tumor called plasmacytoma. Yet in other cases, the myeloma cells accumulate in several bones developing many tumors termed as multiple myeloma. It is also known as plasma cell myeloma, myelomatosis, or Kahler’s disease. In myeloma, unusual plasma cells accumulate collectively in the bone marrow and obstruct the production of normal blood cells (Fonseca and Valdez 2002). n n nAdenocarcinoma is a cancer of epithelial tissue that has glandular origin, glandular characteristics, or both. They form the part of larger grouping of carcinomas. Carcinoma is just not limited to epithelial or skin or glands but a diversity of other tissues that lines the cavities and organs of the body. Thus invasive ductal carcinoma, the most common form of breast cancer, is adenocarcinoma which does not use the term in its name, but esophageal adenocarcinoma does to distinguish it from the other common type of esophageal cancers, esophageal squamous cell carcinoma, which is not adenocarcinoma. Several of the most common forms of cancer are adenocarcinomas, and the various sorts of adenocarcinomas vary greatly in all their aspects, so that few useful generalizations can be made about them. n n nBlastoma arises in embryonic tissue of organs. It is a cancerous tumor that originates from the immature cells that form the basis for an organ’s structure. It occurs in the cells which are undifferentiated, i.e., they have not developed a specific role within the body yet. It usually occurs in childhood and may rarely occur in early adulthood. Though osteoblastoma (blastoma of the bone) is a noncancerous tumor, otherwise most blastomas are cancerous which include nephroblastoma, medulloblastoma, and retinoblastoma (Harada et al. 2006).

Factors Affecting Cancer Development

There are a number of innate and extrinsic features coupled with the progression of cancer. The innate features consist of age and hormonal significance of the individual, ancestral history, and hereditary make. The external features comprise diet and lifestyle, smoking and alcohol use, contact to deadly chemicals and radiation, several infections, etc. A number of agents in external factors are chemical and environmental pollution, dyes, food additives, and exhaust from automobiles functioning as promoters in carcinogenesis (Dibyajyoti 2014). Intrinsic factors also termed as natural features include:

Hallmarks of Cancer Cell

The fascinating complexity of a cancer cell is derived collectively from six basic alterations of cell physiology that result in sustained malignant proliferation (Hanahan and Weinberg 2000). However in in vitro cancer cells, four of the variations are easily detectable in yielding a phenotype of persistent proliferation and aversion from apoptosis. Cell migration/metastasis and angiogenesis are the other two which may be only observed in vivo. Genetic mutations in proto-oncogenes, onco-suppressors, and environmental conditions like hypoxia or inflammation contribute to malignant growth. The loss of tumor suppressor genes (TSG) by mutation may contribute to uncontrolled cell growth leading to cancer. Similarly proto-oncogenes are active in the signaling pathway for cell growth, and on mutation they transform into oncogenes triggering nonstop cell divisions leading to hyper-proliferation. Data implies that tumor cells are different from normal cells in at least six ways relating to growth control: sustaining proliferative signaling, evading growth suppressors, resisting cell death, inducing angiogenesis, invading replicative immortality, and activating invasion and metastasis (Hanahan and Weinberg 2011) (Fig. 2.1).

Cancer Chemoprevention: Hurdles and Future Prospects and Considerations

The disappointing results of chemoprevention trials in human are certainly of concern. Negative results should not discourage us from looking into the positive effects of chemoprevention. However slight advances in cancer chemotherapy catch the attention of the world, and feeble positive results are also measured considerably, unlike in cancer chemoprevention. Another factor is that expectations from chemoprevention are too high and success is barely observed. If chemoprevention is proposed to be the future therapy for cancer, various other factors are required to be calculated seriously.

Modulation of Akt/mTOR Pathway Signaling by Chemoprevention

The PI3K/Akt/mTOR signaling pathway is one of the most repeatedly targeted pathways in all sporadic human cancers which accounts for 30 % of all well-known human cancers. Receptor tyrosine kinases (RTKs) or Ras activates PI3K which in turn activates Akt, its most chosen downstream target, and other several intracellular signaling molecules. Akt phosphorylates an array of substrates resulting in their activation, and the factors that are downstream factors of Akt control four wide processes—cell cycle progression, cell growth, cell metabolism, and cell survival (Luo et al. 2003; Ahmad et al. 2013). mTOR is activated when Akt alleviates the inhibitory action of tumor suppressor tuberin, namely, tuberous sclerosis complex 1 (TSC1) on mTOR. Therefore, the PI3K/Akt/mTOR pathway plays a vital role in the cell growth and metabolism once activated and eventually is involved in the invasion, metastasis, and aggressiveness of cancer cells. Hence this pathway could be targeted as a novel therapeutic option for better prognosis in cancer patients and its defined role in more than a quarter of known cancers (Manning and Cantley 2003; Falasca et al. 2011).

Chemoprevention by Epigallocatechin-3-Gallate (EGCG)

Tea that is obtained from leaves of the plant Camellia sinensis is subsequent to water and is the most extensively consumed drink in the world. Black, green, and oolong tea are the forms which are produced by the different processing and manufacturing techniques making them chemically different from each other resulting for around 75 %, 23 %, and 2 % of the global production, respectively (Kavanagh et al. 2001). Black tea is a rich source of complex antioxidants called theaflavins and thearubigins, whereas steamed and dried green tea contains simple antioxidants called catechins. Green tea has been used for centuries to treat and prevent chronic diseases in traditional Chinese medicine, but it is only lately known as an efficient chemopreventive agent against various cancers (Sueoka et al. 2001).

Clinical Trials of Chemoprevention

Since the 1980s, numerous large randomized clinical chemoprevention trials have been carried out. Breast and prostate cancer and FAP demonstrated positive results, while lung and colon cancer demonstrated negative results for the agents under investigation which taught some important lessons in the domains of trial design, selection of chemopreventive agents, and doses for future trials.

Chemoprevention by Resveratrol

Resveratrol is a naturally occurring polyphenol found abundantly in red grapes and red wine. It has been found to be antioxidant, anti-inflammatory, anti-carcinogenic, and antibacterial from the extensive research during the last two decades. It modulates various multiple biological pathways and hence exerts its chemopreventive and chemotherapeutic effects (Chung et al. 2013).