Together these activated proteases MMPs and

Together these activated proteases MMPs and cathepsins, along with other enzymes (as mentioned above) in their pathways start the pathologic cascades, causing epigenetic changes and tissue remodeling, setting the stage for tumorigenesis (Page-McCaw et al., 2007). There are numerous other known and unknown enzymes participating in the pathologies. Fig. 2 illustrates the mechanism. Several cancer-associated receptor proteins, the G-protein-coupled receptor (GPCR) such as ovarian cancer G-protein-coupled receptor 1 (OGR1), and GPR4, promote the inflammatory enzyme expression, and T-cell death-associated gene 8 (TDAG8) act as a proton-sensing receptor (Ihara et al., 2010, de Vallière et al., 2015). In acidic conditions, these enzymes are activated. Transcription factors are activated with change in pH, which modulates their activity via p38 MAPK activity (Riemann et al., 2011). Cancer-associated transcription factors involved in the enzyme activation include AP-1 (activator protein 1), Nuclear factor κappa B (NF-κB), hypoxia inducible factor (HIF), p53, STAT, GATA3, FOXA1, FOXA2, SOX17, NFE2L2, SOX2, TP63, SP1, BCLAF1, E2F4, and NFATc2 (Gerlach et al., 2012, Paquin et al., 2013, Liu et al., 2015, Yao et al., 2015). DNA methylation, DNA binding, Cefepime Dihydrochloride Monohydrate progression, T-cell activation, apoptosis, and autophagy are the mechanisms intervened (Gerlach et al., 2012, Paquin et al., 2013). The transcription factor p53 accumulates in hypoxic condition. However, its transrepression activity is enhanced, which inhibits a series of genes (Zhao et al., 2009). In this regard, p53 antagonizes HIF genes, which normally are involved in metastasis (Zhao et al., 2009, Rankin and Giaccia, 2016). Drug resistance to both pathogens and cancer has been a big hindrance in healthcare. Integrated research undertakings are being pursued to find the exact causes of the lack of response towards drugs. Surprisingly, host pumps are the key factors in failure of most drugs. The pumps either do not allow penetration of drugs into or eject them from pathogens or tumor cells. Sub-lethal dosage of drugs lead to pathogen viability in host and promote tumor progression. Among the ATP-dependent efflux pumps, p-glycoprotein (P-gp) is a well-studied one (Germann et al., 1993, Leonard et al., 2003, Damiani et al., 2006). Its activity is increased by low intracellular calcium levels and high acidic pH (Thews et al., 2006). In the wake of its role in drug-purging from the target cells, its inhibitors are being searched for. Several natural products are showing P-gp-inhibitory activity. Some phytochemicals capable of its inhibition include quercetin, emodin, 18β-glycyrrhetic acid, and 20(S)-ginsenoside (Li et al., 2014). However, P-gp suppression is not an easy solution as it is widely distributed in human body and performs crucial functions like keeping cell safe from potential threats as toxins, xenobiotics, pollutants, mutagens etc. (Amin, 2013). In fact, P-gp is the factor which regulates bioavailability as well (Amin, 2013).