Abstract: An Adenosquamous lung (lung cancer) with metastasis is considered as a major leading cause for death in India and around world. Modern drug-targeted therapies have undoubtedly improved treatment to the patients but also have evoked severe side effects such as loss of hairs, weakness, loss of eye sight, vomiting and headache. Organ failure and immunosuppression due to the modern drug-targeted therapies are also the reasons for death of the adenosquamous lung patients. However, the advanced stage of adenosquamous lung with metastasis remained untreatable at present. So, there is a need for the safer and cost effective drugs with enhanced efficacy. The herbal therapies are being advocated in order to address the above-mentioned issues. The active ingredients of herbal compounds have been reported to detoxify and remove reactive substances generated by carcinogenic agents. The phytochemicals are known to possess anti-proliferative, anti-mutagenic and anti-carcinogenic properties and therefore have the potential to induce death of adenosquamous lung cells. A thorough search of the scientific literature available till date was carried out independently in the scientific databases and search engines such as Cochrane Library, Embase, Medline, PubMed Central, Web of Science and the libraries for original researches. In our analysis, the data were independently extracted by using standard data extraction method. Phytochemicals or plant-based principles are being exploited as emerging strategies for the prevention, delaying and/or impeding the occurrence of lung cancer and also curing the patients. This review summarizes an updated account of research in adenosquamous lung treatment strategy employing phytochemicals from Indian traditional medicinal plants.
INTRODUCTION
Cancers are recognised as abnormal growth of cells. Cancer develops through an accumulation of mutations emerged due to exposure of an individual to different factors such as UV and other radiations, chemicals and biological entities. In some cases it may be hereditary. The types of damages within DNA including strand breaks, various forms of base damage in DNA may be induced by free radicals resulting into a heritable change in the genetic material i.e., DNA, thereby causing development of cancer. Different types of free radicals, reactive oxygen species (ROS) and reactive nitrogen species (RNS), have been reported to react with the biomolecules1, leading to the onset of cancer2. Earlier cancers were reported only in developed countries but now developing countries are also getting affected3. According to the World Health Organization (WHO) the percentage of diagnosed cancer cases in developing countries may increase by more than 60% in 20304. In general, the lifestyle has been known to be the major factors for cancer development in developing countries including India.
In India, the death due to the adenosquamous lung (lung cancer) is one of the most prominent causes among cancer patients. The prevalence of smoking is declining in developed countries5 and rising in the developing countries. This could be the main cause of increase in burden of cancer in developing countries6. Several studies have been conducted for the treatment of the lung cancer using herbal products but still lot more is required to be done to formulate it in the form of the established drugs. Therefore, an endeavor has been made in this communication to study and present an updated account of the phytochemicals as an alternative medicine with almost no side effects as anticancer agents in general and for the treatment of adenosquamous lungs in particular.
Prevention and treatment for adenosquamous lung by phytochemicals: Prevention of a disease is always considered superior approach than its cure. A large number of medicinal herbal plants have been reported to prevent and treat various diseases for thousands of years7. The naturally occurring bioactive chemical components derived from plants have been reported to be exerting their beneficial effects and have also been confirmed for their anti-cancerous activities (Table 1)8-62. Also, the variety of nutritional factors including vitamins A, C and E, as well as beta-carotene, micronutrients and different phytochemicals found in edible and non-edible plants can act as anti-cancer agents and inhibit the process of cancer development7.
Interaction of phytochemicals with adenosquamous lung cells: Many phytochemicals have been reported to activate and target the apoptosis pathways in cancer cells63. The apoptosis mechanism involves several signalling pathways. The apoptotic proteins cause mitochondrial swelling and increase the permeability of the mitochondrial membrane64. Small mitochondrial derived activators of caspases (SMACs) are released from mitochondria into cytosol. These activators bind to inhibitor of apoptosis proteins (IAPs), inactivate IAPs and prevent them from arresting the apoptotic processes. Caspases, which carry out the cell degradation and are suppressed by IAPs, proceed for cell apoptosis process65. Caspase activators (such as cytochrome c and SMAC) can be released from the mitochondrial membrane when the pro-apoptotic homodimers are formed in the outer-membrane of the mitochondrion. Inhibitor caspases (caspase 2, 8, 9 and10) may require certain adaptor proteins. Cytochrome c released from mitochondria due to the formation of mitochondrial apoptosis-induced channel (MAC) in the outer membrane of mitochondria binds with apoptotic protease activating factor-1 (Apaf-1) and ATP. This assembly then binds to pro-caspase-9 followed by the formation of an apoptosome which is then followed by the activation of caspase-366. The activation of caspases 3 promote the cell death processes.
Cyclooxygenases (COX-2) are bi-functional membrane-bound enzymes66,67. COX-2 contained a number of upstream regulatory sequences specific for binding with a variety of transcription factors, such as NF-κB, SP-1 and activator protein-1 (AP-1)67. These transcription factors could be the final executors for a number of intracellular signaling pathways. Housekeeping function mediated by COX-1 and COX-2 is low in most cells but may be constitutively elevated in lung cancers. COX-2 may be induced at very early stage of lung cancer development therefore the prevention of its aberrant expression may prevent the formation of lung cancer.
Hedgehog signaling pathway (HSP) has been reported to be involved in providing the instructions to the cells for their proper development. The abnormal activation of this pathway may give rise to cancer through transformation of adult stem cells into cancer stem cells. Therefore, the researchers are looking for specific inhibitors of this pathway to devise an efficient cancer therapy68. The activation of Hedgehog signaling pathway results into the increased angiogenic factors and decreased apoptotic genes39,70. Therefore, this pathway has been considered as a target pathway for the treatment of several cancers71.
NF-κB is a family of rapid-acting primary transcription factors.
| Table 1: | Phytochemicals from medicinal plants, their sources and anticancer functions against different cancers |
They are present in inactive state inside cells and do not require new protein synthesis to get activated, which allows them to be the first responder to harmful stimuli. Blocking NF-κB may cause tumor cells to stop proliferating, become more sensitive to the action of anti-cancer agents and finally to die72.
Nrf2 is a basic leucine zipper (bZIP) transcription factor and under normal condition, Nrf2 is tethered in the cytoplasm by the Kelch like-ECH-associated protein 1 (Keap1)73. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a transcription factor that regulates antioxidant responses72.
Phosphatidylinositol 3-kinases (PI3Ks) are a family of enzymes involved in cell growth, proliferation, differentiation, survival and intracellular trafficking. The activation of PI3Ks may significantly contribute to the cellular transformation and the development of cancer. Inhibition of PI3Ks could be an important therapeutic strategy for suppressing cancer development74.
Signal transducer and activator of transcription 3(STAT 3) is a transcription factor that plays a key role in cell growth and apoptosis. The constitutive STAT3 activation has been reported to be associated with poor prognosis, anti-apoptotic and proliferative effects in the cancer cells75.
The modifications in Wnt signalling pathway has also been reported to be associated with carcinogenesis. The Wnt proteins exert their effects in embryonic development, cell differentiation and generation of cell polarity by activating various other pathways76.
In addition, there are several mechanisms reported for apoptosis of lung cancer cells such as human epidermal growth factor receptor (HEGRR2) in breast cancer77, hypoxia-induced factor-1α, MMP-9 expression in colon cancer and mevalonate pathway78. Many natural dietary phytochemicals have been studied for cancer prevention and treatment. These native phytocompounds have guided continuing research to bring them into the market as anticancer agents. Application of phytochemicals to cancer patients for chemoprevention encounters an immediate challenge in terms of their effects on human health and bioavailability. Though the chemical structures of some phytochemicals are well understood, their physicochemical properties are not well documented as yet and it needs detailed investigation.
CONCLUSION
Phytochemicals in treatment of adenosquamous lung are considered as the cheapest option. Phytochemicals have been widely used in preclinical cancer prevention and treatment studies. Phytochemical agents are believed to play significant roles in controlling, inhibiting and blocking signals which can cause translation of normal cells to cancer cells. The prevention or treatment of adenosquamous lung using phytochemicals has been an attractive approach. However, more efforts should be made to thoroughly understand their potencies, pharmacokinetics, pharmacodynamic responses, metabolisms, toxicities, drug-drug interactions, polymorphisms, formulations and doses and to explore the molecular mechanisms of phytochemicals in the treatment. In the adenosquamous lung phytochemical agents many cause changes in chromatin conformation, disrupt the redox balance between cells and deregulate the proteins involved in DNA repair mechanism and hence might activate the DNA damage response in cancer cells more effectively as compared to the normal cells. It is expected that the improved understanding of these mechanisms may provide a more rational basis for combining specific dietary compounds and radiation therapy or chemotherapy approaches to treat the disease. More studies are required to be carried out on dose-dependent responses in order to evaluate the toxicity of the phytochemicals, if any, to ascertain their safety before usage.
ACKNOWLEDGMENTS
The author (VKG) is grateful to the Indian Council of Medical Research-New Delhi for providing research scholarship. The Department of Biochemistry, University of Allahabad is supported by FIST grant from Department of Science and Technology, New Delhi, India and SAP-DRS grant from University Grants Commission, New Delhi, India.