Drug resistance to both pathogens and cancer
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 Dorsomorphin (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).
Discussion In fact, the drugs-cancer link is not straightforward. Several anticancer drugs increase ROS production (Peng and Gandhi, 2012), which creates hypoxia (McKeown, 2014). It favors the tumors, as they are adapted to survive in hypoxic conditions (Rockwell et al., 2009, McKeown, 2014). The hypoxic milieu promotes malignancy progression. Conflicting results abound when it comes to therapeutic success. COX-2-targeting non-steroidal inflammatory drugs (NSAIDs) have been seen to lower cancer incidences (such as that of breast cancer) (Bowers et al., 2014). On the other hand, several drugs create ROS and generate hypoxic condition, ideal for some tumor proliferation. In the face of such dual, opposing behavior, therapeutic regimen cannot be standardized. Rather than finding inhibitors for different checkpoints, the upstream issues ought to be targeted. Manipulation of the extracellular pH is presumed to prevent downstream pathological activities (McCarty and Whitaker, 2010). In vitro administration of non-volatile buffer have already shown anti-metastases role (Ibrahim-Hashim et al., 2011). Acidosis induces MAPK phosphorylation and consequent pathologies (Riemann et al., 2011), but the same MAPK signaling pathway in alkalosis confers protection (Stathopoulou et al., 2006). The pH is a very sensitive and critical parameter, not only for human, but for every living organisms. Rising oceanic acidity is killing coral reefs (Schmidt, 2008) and inorganic fertilizer-caused drastic soil pH change has been known to decimate beneficial soil microbes (Zhang et al., 2015). Hence, one ought to follow a stressor-free lifestyle so as not to create an extracellular acidic milieu. But then how to lower the in vivo extracellular acidity? As any kind of drugs can add fuel to the vicious cycle of oxidative stress, they are not an option. Diet and exercise might be the answer. Some food articles like salt, meat, dairy products, grains, soft drinks, and chocolates are acidogenic (Jehle et al., 2006, Schwalfenberg, 2012). Unfortunately, the dietary mainstay in Western World is dominated by the acidogenic foods (Scialla and Anderson, 2013). Also, food additives as sulphites, nitrites, benzoic acid, emulsifier agents (polysorbate-80) and colors are fueling inflammation and raising acidity (Singh et al., 2016). Such food intake ought to be lowered or eliminated from diet (Robey, 2012). Studies have already found that the consumption of alkali foods as citrate salts have beneficial effects on bone mass (Jehle et al., 2006). Plant-based, phytochemical-rich food might alleviate ROS (Kon et al., 2010, Kumar and Khanum, 2012, Grabacka et al., 2014). It has been consistently found that the dietary acid load is lower with greater intake of fruits and vegetables (Scialla and Anderson, 2013). In fact, human body has evolved to its present form by the ingestion of alkalogenic diet dominated by fruits, tubers, nuts etc. as was the mainstay in the hunter-gatherer (Paleolithic) stage (Liu et al., 2013), long before agriculture, animal domestication and industrialization shifted food habits towards acidogenic diet. Also, in contemporary time Mediterranean food is hailed as healthiest among other diets for its alkalogenic ingredients (Dontas et al., 2007, Altomare et al., 2013, Del Chierico et al., 2014, Castro-Quezada et al., 2014). Dietary correction appears to be the most convenient approach to manage acidity and to keep cancer and other pathologies at bay. Though, as everything else in biology, it is not an easy solution. For example, dairy products like cheese and butter are acidogenic, but they provide vitamin D, which is needed for health (Schmid and Walther, 2013). Inhalation of oxygen by ample physical exercise might nullify the adverse effect of hypoxia. Quitting addictive habits as smoking, alcohol and substance misuse can ease stress on body. Chemicals like fragrance compounds, personal care products, food additives, and pesticides are major stressors which trick the body\'s surveillance system into believing that stress looms. To tackle the threats, body modulates its components, creating a acidic milieu. So, leaning towards a natural living pattern can prevent acidosis.