Phytochemicals and phytotherapy for cancer precision medicine

Abstract (as presented by the authors of the scientific work):

"Concepts of individualized therapy in the 1970s and 1980s attempted to develop predictive in vitro tests for individual drug responsiveness without reaching clinical routine. Precision medicine attempts to device novel individual cancer therapy strategies. Using bioinformatics, relevant knowledge is extracted from huge data amounts. However, tumor heterogeneity challenges chemotherapy due to genetically and phenotypically different cell subpopulations, which may lead to refractory tumors. Natural products always served as vital resources for cancer therapy (e.g., Vinca alkaloids, camptothecin, paclitaxel, etc.) and are also sources for novel drugs. Targeted drugs developed to specifically address tumor-related proteins represent the basis of precision medicine. Natural products from plants represent excellent resource for targeted therapies. Phytochemicals and herbal mixtures act multi-specifically, i.e. they attack multiple targets at the same time. Network pharmacology facilitates the identification of the complexity of pharmacogenomic networks and new signaling networks that are distorted in tumors. In the present review, we give a conceptual overview, how the problem of drug resistance may be approached by integrating phytochemicals and phytotherapy into academic western medicine. Modern technology platforms (e.g. "-omics" technologies, DNA/RNA sequencing, and network pharmacology) can be applied for diverse treatment modalities such as cytotoxic and targeted chemotherapy as well as phytochemicals and phytotherapy. Thereby, these technologies represent an integrative momentum to merge the best of two worlds: clinical oncology and traditional medicine. In conclusion, the integration of phytochemicals and phytotherapy into cancer precision medicine represents a valuable asset to chemically synthesized chemicals and therapeutic antibodies."


Covered topics (the letter size corresponds to the frequency of mentioning in the text):

Conclusions and perespectives (as presented by the authors of the scientific work):

"The fact that chemosensitivity testing was not established as routine laboratory method may have historical reasons. In times as combination therapy protocols were established as being superior to monotherapy, data showing that tumors can reveal resistance towards many drugs at the same time was compromising the utility of drug combination regimens.
On the one hand, clinical experiences showed combination therapy protocols were able to improve treatment results, but sustainable use of patients from cancer is far from reality in many cases. On the other hand, molecular mechanisms were discovered in basic sciences that explained the appearance of broad spectrum resistance phenomena (e.g. ABC-transporter-mediated multidrug resistance, apoptosis resistance etc.). A re-thinking may lead to a revival of predictive testing. Rather than prediction of drug sensitivity (which is not sufficiently reliable), drug resistance can be predicted with high precision. With multi-modal treatment options at hand, the knowledge about high probability that a specific drug would fail in a specific patient is valuable, because it allows early to switch to other more effective drugs or therapy strategies.
The development of resistance and the severe side effects of classical cytotoxic cancer therapy lead to a paradigm shift from the poorly specific cytotoxic anticancer drugs to targeted drugs, which were expected to be more tumor-specific. Indeed, this turned out to be a thriving concept with numerous new drugs on the market, which of course did not replace the classical cytotoxic drugs, but did supplement the armory to fight cancer. Although treatment outcomes could be further improved by targeted drugs they unfortunately also reveal side effects and are subject to resistance development. In this context, the therapeutic potential of phytochemicals cannot be overseen. They were already valuable in the era of cytotoxic drugs. Paclitaxel, vincristine, camptothecin, etoposide are just a few examples for established plant-drived anticancer drugs. There is a plethora of literature demonstrating that phytochemicals are also valuable for targeted cancer therapy.
Cancer stem-like cells are rare self-renewing omnipotent cells, which proliferate upon appropriate stimulation and differentiate into heterogeneous lineages in tumors. They are frequently resistant to conventional chemo- and radiotherapy. Interestingly, natural products have been described to inhibit cancer stem-like cells [103-107]. This is a new field of research that is worth being investigated in more detail to understand the full range of mechanisms, which are responsible why some natural products are able to attack stem-like cells.
With the recent developments in bioinformatics, network pharmacology emerges as novel concept in therapy research. Phytotherapy with mixtures of several herbs as well as isolated single compounds exert their bioactivity by targeting multiple sites in diseased cells. A challenge for research in network pharmacology will certainly be to extract meaningful information from thousands of data points. What is a mechanistically relevant signal and what is background noise? Finding the needle in the haystack will be a task for the future and smart computer algorithms are required. Network pharmacology has to cope with multiple dimensions of problems. The multi-targeted nature of drug action, resistance development, side effects on normal organs and tissues, inter-individual biological variations, as well as inter- and intra-tumoral differences have to be considered. Especially the problem of tumor heterogeneity and possibilities to tackle with genetically diverse tumor subpopulations deserve attention from our point of view. Heterogeneous tumor populations represent a main reason for the development of resistant refractory tumors. Resistance also prevents to apply doses high enough to kill all cells, because of the severe side effects of anticancer drugs. Therefore, novel strategies to eradicate heterogeneous tumor subpopulations might not only fight the development of drug resistance but also facilitate to reduce side effects.
Integrating precision medicine into routine cancer therapy is certainly one of the predominant tasks of the next years to come (Figure 6). To realize this concept, it is not only necessary to establish the scientific basis allowing routine application in the clinic, but also to develop and integrate economic models, which allow the implementation of personalized medicine [108-111]. This is true independent of whether synthetic drugs or phytotherapeutic approaches will be used. While there is a plethora of literature on the preclinical activity of phytochemicals and medicinal plant preparations, results from clinical trials are still relatively rare. However, there are well-done clinical trials that provide evidence that phytochemicals and plant preparations are indeed active in the clinical setting [111-119]. For the sake of future patients, health care systems in industrialized and developing countries should do any effort to improve cure rates of tumor diseases."


Full-text access of the referenced scientific work:

Efferth T, Saeed MEM, Mirghani E, Alim A, Yassin Z, Saeed E, Khalid HE, Daak
S. Integration of phytochemicals and phytotherapy into cancer precision medicine.
Oncotarget. 2017 Apr 27. doi: 10.18632/oncotarget.17466. [Epub ahead of print]
Review. PubMed PMID: 28514737.
http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=17466&path%5B%5D=55890


Further reading:

Precision medicine (Wikipedia):
"Precision medicine (PM) is a medical model that proposes the customization of healthcare, with medical decisions, practices, or products being tailored to the individual patient. In this model, diagnostic testing is often employed for selecting appropriate and optimal therapies based on the context of a patient’s genetic content[1] or other molecular or cellular analysis. Tools employed in precision medicine can include molecular diagnostics, imaging, and analytics.[2]
...read more".

Cancer (MedlinePlus):
"Cancer begins in your cells, which are the building blocks of your body. Normally, your body forms new cells as you need them, replacing old cells that die. Sometimes this process goes wrong. New cells grow even when you don't need them, and old cells don't die when they should. These extra cells can form a mass called a tumor. Tumors can be benign or malignant. Benign tumors aren't cancer while malignant ones are. Cells from malignant tumors can invade nearby tissues. They can also break away and spread to other parts of the body.
Cancer is not just one disease but many diseases. There are more than 100 different types of cancer. Most cancers are named for where they start. For example, lung cancer starts in the lung, and breast cancer starts in the breast. The spread of cancer from one part of the body to another is called metastasis. Symptoms and treatment depend on the cancer type and how advanced it is. Most treatment plans may include surgery, radiation and/or chemotherapy. Some may involve hormone therapy, immunotherapy or other types of biologic therapy, or stem cell transplantation.
...read more".

Phytotherapy (Encyclopaedia Britannica):
"Phytotherapy, the use of plant-derived medications in the treatment and prevention of disease. Phytotherapy is a science-based medical practice and thus is distinguished from other, more traditional approaches, such as medical herbalism, which relies on an empirical appreciation of medicinal herbs and which is often linked to traditional knowledge. An herbalist’s approach generally has not been evaluated in controlled clinical trials or in rigorous biomedical studies, whereas numerous trials and pharmacological studies of specific phytotherapeutic preparations exist. The interpretation and acceptance of such evidence for phytotherapeutic practices varies. In some countries, it is considered sufficient to license phytotherapeutic products as medicines, whereas in other countries, phytotherapy is viewed as a form of traditional medicine.
...read more".

Phytochemical (Wikipedia):
"Phytochemicals are chemical compounds produced by plants, generally to help them thrive or thwart competitors, predators, or pathogens. The name comes from the Greek word phyton, meaning plant. Some phytochemicals have been used as poisons and others as traditional medicine.
As a term, phytochemicals is generally used to describe plant compounds that are under research with unestablished effects on health and are not scientifically defined as essential nutrients. Regulatory agencies governing food labeling in Europe and the United States have provided guidance for industry limiting or preventing anti-disease claims concerning phytochemicals on food product labels.
...read more".


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