Natural compounds as potential adjuvants to cancer therapy: Preclinical evidence

Abstract

1. INTRODUCTION

In clinics, chemotherapy for cancer patients is commonly based on the drug indications, recommended dosages, treatment duration, and adverse effects (e.g., nephrotoxicity and hepatotoxicity; Grossi et al., 2010; Sharbaf, Farhangi, & Assadi, 2017; Sulthana et al., 2017). Occasionally, it is difficult to prevent occurrences of adverse effects from chemotherapeutic drugs during therapy. For instance, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7069, a widely used chemotherapy agent, frequently induces cardiomyopathy and chronic heart failure with a prevalence between 4% and 36% (cardiomyopathy) and 0.2–8.7% (chronic heart failure) according to cumulative doses (Chatterjee, Zhang, Honbo, & Karliner, 2010; Volkova & Russell, 2011; J. Yu et al., 2018). Although there are reports of nephrotoxicity and immunosuppression from http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5343 during treatment, it is, nevertheless, a first choice for the treatment of advanced non‐small‐cell lung cancer cells (NSCLC), breast cancer and ovarian cancer (Brown et al., 2013; Browning et al., 2017; Lorusso, Petrelli, Coinu, Raspagliesi, & Barni, 2014; Manohar & Leung, 2018). Moreover, cancer cells may develop drug resistance during treatment with chemotherapy. Accordingly, higher doses need to be applied to achieve a similar tumoricidal effect as the initial dosage. Frequently, higher dosages have a higher possibility of severe side effects (Zheng, 2017). Consequently, taking a combination of drugs with different mechanisms could synergistically potentiate therapeutic efficacy (Glasgow & Chougule, 2015).

Currently, combinations of chemotherapeutic drugs are widely used for various cancer types (Liu et al., 2017; Zhang et al., 2011). Importantly, the advantage of using multiple drugs are seen as the lowering of doses which could lead to lower resistance and the retention of the same efficacy or sometimes a higher efficacy, a synergistic effect (Glasgow & Chougule, 2015; He et al., 2015; Liboiron & Mayer, 2014). The effects of lower toxicity are ignored as they are considered to be harmless. In fact, the accumulation of toxicity from each drug can still cause deleterious systemic responses (F. Li & Zhang, 2015). Therefore, optimizing drug ratios and schedules can provide an opportunity to improve drug combination activity and reduce dosages to attenuate toxicity (L. Wu, Leng, Cun, Foged, & Yang, 2017). Additionally, drug combinations which include dietary supplements and natural products have been postulated to obtain similar effects to conventional chemotherapeutic drugs but with less adverse effects (Lin, Fu, Tsai, Cheng, & Weng, 2017). Three meta‐analyses reviewing traditional herbal medicine have found such products used as chemotherapeutic adjuvants in nasopharyngeal, breast, and pancreatic cancer treatments. The effective outcome has exemplified traditional herbal medicine as a chemotherapeutic adjuvant (W. Kim, Lee, Lee, Min, Baek, et al., 2015a; W. Kim, Lee, Lee, Min, Lee, & Cho, 2015b; Kuo et al., 2018). Since 2006, several clinical trials were conducted to assess the enhancing effect of natural compounds such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7000 or traditional Chinese medicine (TCM) in promoting conventional chemotherapy against various cancers, including lung cancer (especially non‐small‐cell lung cancer), breast cancer, and colon cancer (Table ​(Table1).1). The conventional chemotherapeutic drugs used in these clinical trials include the platinum‐based chemotherapeutic drugs (e.g., cisplatin and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7433), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4793, and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6809. These drugs can cause severe side effects during therapy such as nephrotoxicity caused by cisplatin and a high prevalence of haematopoiesis suppression by gemcitabine (Manohar & Leung, 2018; Takei et al., 2017). Although some of the clinical trials were complete, none of the results was reported in detail (Table ​(Table1).1). The aim of this article is to highlight recent preclinical evidence on the potential of natural products as adjuvants in cancer therapy.

2. HERBAL COMPOUNDS WITH THE POTENTIAL TO SYNERGIZE WITH ANTITUMOR DRUGS

A synergistic effect is described as an increase in efficacy for a combination of components when compared with a single one (Pai, Cottrell, Kashuba, & Bertino, 2015). Data focusing on the toxic episodes of chemotherapy has led to the characterization of novel strategies, including the exploitation of natural compounds in combination therapies. The goals of including natural compounds in cancer chemotherapies are as follows: (a) to widen the therapeutic window of the chemotherapeutic drugs and (b) to decrease the occurrence of chemotherapy resistance (Ouyang et al., 2014). The next section will summarise herbal or folk medicines and natural compounds that act as chemosensitizers, chemoresistance reducers, or chemotherapeutic protectors, in clinical use.

2.2. Herbal compounds reduce resistance against cancer therapy

Clinically, herbal compounds can reduce resistance against cancer therapies, and this has become a critical concern. Up to now, drug resistance (excluding radiation‐resistance) in cancer cells remains the most challenging aspect of cancer treatment, especially in NSCLC and prostate cancer (Chang, 2011; Wade & Kyprianou, 2018). Such resistance in cancers reveals a transformation of cancer cells from drug susceptible to resistant, which leads to higher toxicity and expenditures in treatments (Housman et al., 2014; Zheng, 2017). About 90% of treatment failures in recurrent cancer therapy and 80–90% of cancer death is strongly correlated to cancer resistance (Mansoori, Mohammadi, Davudian, Shirjang, & Baradaran, 2017; Yuan et al., 2017).

Prevailing mechanisms of chemoresistance are classified into seven phases: drug flux, DNA damage repair, cell death inhibition, epithelial‐mesenchymal transition (EMT), drug target alteration, drug inactivation, and epigenetics (Housman et al., 2014), and notably, drug flux is the most concerned issue in this topic. Cancer cells pump chemotherapeutic agents out of the cells using the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=153 (MRPs, also known as MDR or the ABCC family of transporters) and the Hedgehog receptor Patched 1 (protein patched homolog 1, PTCH1), which reduces drug accumulation within cancer cells and, thereby, lower drug efficacy (Amiri‐Kordestani, Basseville, Kurdziel, Fojo, & Bates, 2012; Bidet et al., 2012). MRPs, particularly http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=779 (also known as p‐glycoprotein, P‐gp), are found over‐expression in recurrent cancer cells and which over‐expression is associated with poor prognosis (Chen et al., 2016; W. Li et al., 2016). PTCH1 is a newly discovered drug efflux transporter also found to be overexpressed in many metastatic cancers (Hasanovic & Mus‐Veteau, 2018). In addition to drug efflux, PTCH1 also acts as a receptor in Hedgehog/Gli signalling pathway that activates http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=239 (Smo)/Gli transduction and leads to growth factor expression (Armas‐Lopez, Zuniga, Arrieta, & Avila‐Moreno, 2017; Rimkus, Carpenter, Qasem, Chan, & Lo, 2016). Some chemotherapeutic agents specially target growth factor signalling, for example, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4941 (Iressa®, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1797 inhibitor), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5082 (Herceptin®, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2019/neu inhibitor), and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6771 (Avastin®, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=324 inhibitor; National Cancer Institute, 2002a, 2002b). However, cancer cells turn on EMT, which leads to anoikis resistance and continuous activation of growth factor signalling during cancer invasion (J. Wang et al., 2016). EMT‐induced chemoresistance has been identified in several cancer types, including lung cancer, prostate cancer, and breast cancer (Fischer et al., 2015; J. Huang, Li, & Ren, 2015; Wade & Kyprianou, 2018).

Numerous cancer drugs, including platinum‐based chemotherapeutic drugs, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7242, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6823, and doxorubicin, belong to the group known as DNA damage agents (Cheung‐Ong, Giaever, & Nislow, 2013). Therefore, DNA repairing capacity would directly affect these cancer drugs' effects (Nagel et al., 2017; Sakthivel & Hariharan, 2017). However, Wang et al. have explored the involvement of Wip1, which is an inhibitor of the http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1934 kinase‐mediated DNA repairing system, in cancer resistance of oral squamous cell carcinoma (OSCC). Wip1 activation is thought to potentiate the cytotoxicity of cisplatin against OSCC (L. Wang, Mosel, Oakley, & Peng, 2012). Unexpectedly, a positive correlation between Wip1 expression and cisplatin resistance in OSCC has now emerged (L. Wang et al., 2012). Thus, both positive and negative relationships between DNA repairing mechanisms and chemoresistance have been found and further investigation is needed to clarify the characteristics of DNA repairing mechanisms in chemoresistance. Figure ​Figure11 summarizes the above discussion, showing seven mechanisms of chemoresistance proposed, and giving examples of chemotherapeutic drugs affected by particular chemoresistance mechanisms.

Open in a separate window

Figure 1

Recent‐known mechanism of chemoresistance

Recent studies on the effects of natural compounds against chemoresistance show that they inhibit MDR protein activity or further reduce MDR protein expressions (Turrini, Ferruzzi, & Fimognari, 2014). Table ​Table22 lists these MDR inhibitors and compounds acting through other mechanisms. This Table shows that MDR inhibition accounts for the highest rate. Interestingly, silybin, a natural lignan isolated from Silybum marianum, allows doxorubicin to overcome drug resistance in colorectal cancer by inhibiting http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=875 (GLUT1) expression. GLUT1 expression could be regulated by the Wnt/http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5371 signalling pathway that has been identified as a cisplatin resistance promoter through the ATM‐mediated signalling pathway in laryngeal squamous cell carcinoma cells (L. Wang et al., 2019). Eleven different polyoxypregnanes isolated from Marsdenia tenacissima can combat doxorubicin resistance in multidrug resistance cancer cell lines via inhibition of ABC transporters (To et al., 2017). A series of bisbenzylisoquinoline alkaloids inhibit the transporter P‐gp, which leads to high doxorubicin accumulation in MCF‐7/ADR breast cancer cell to provide much increased cytotoxicity (Sun & Wink, 2014). Investigation of the antitumor activity of six ergot alkaloids from Claviceps purpurea, showed that these ergot alkaloids might bypass chemoresistance mechanisms through unknown signalling pathways in multiple cancers (Mrusek, Seo, Greten, Simon, & Efferth, 2015). Additionally, ellagic acid and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8741 prevented induction of resistance in ovarian cancer towards cisplatin (Engelke, Hamacher, Proksch, & Kassack, 2016). (Z)‐3,4,3′,5′‐tetramethoxystilbene, a stilbenoid, increased antitumor efficacy of cisplatin in cisplatin‐resistant osteosarcoma cells in in vitro and in vivo (H. Xu, 2016), and another stilbenoid, resveratrol, increased cisplatin uptake and efficacy (Osman et al., 2015). β‐Phenylethyl isothiocyanate and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2428 down‐regulated intracellular http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6737 level and concurrently reversed resistance to doxorubicin and cisplatin in resistant‐uterine sarcoma cells (Angelini, Conti, Ciofani, Cuccurullo, & Di Ilio, 2013; W. J. Wu et al., 2013). Taken together, the data suggest herbal compounds exert beneficial effects in the treatment of recurrent cancers, when combined with current therapies.

3. HERBAL TOXICITIES AND FUTURE REMARKS

An increasing number of cases require closer attention to the additional toxicity induced by the herbal component or by the herbal–drug combination (Table ​(Table3).3). In these examples of herbal‐induced drug injury, some popular formulations or compounds are included, such as curcumin and chokeberry, which is usually used for increasing patient stamina to overcome the adverse effects of cancer therapy. A meta‐analysis has collected 97 herbal‐induced toxicity cases in Korea and found that both single and multiple herbal preparations could induce hepatocellular toxicity, including Polygonum multiflorum and Dictamnus dasycarpus (W. J. Lee, Kim, Lee, & Son, 2015). A following review collects studies about monoterpene‐ and susquiterpenes‐induced hepatotoxicity and summarize that some common terpenes (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2422 and limonene) might injure liver through generating ROS and imparing antioxidant defenses (Zarybnicky, Bousova, Ambroz, & Skalova, 2018). In addition to ROS generation, another hepatotoxic mechanism is simultaneously observed through the modulation of cytochrome P450 (Brewer & Chen, 2017). Coumarins, furanocoumarins, (−)‐epigallocatechin‐3‐gallate, and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2489 have all demonstrated a potent inhibition of cytochrome P450 isoforms, especially http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1337 which is a key enzyme for oral drug detoxification, and MDRs, which may be inhibited and thus prolong the t _1/2 of the drug (Brewer & Chen, 2017; Pal & Mitra, 2006; Shamsi, Tran, Tan, Tan, & Lim, 2017). These findings of toxicity from using herbal medicine for cancer therapy suggest that precautions should be taken against the herb‐induced or drug‐induced liver injury.

Accordingly, the best fit between possible adverse effect and anticancer efficacy is urgently needed in terms of clinical application. The balance between adverse effect and anticancer efficacy can be discussed at two levels, acute and chronic toxicity. Acute toxicity, especially hepatotoxicity, nephrotoxicity, and cardiotoxicity, could be determined during administration. Cardiotoxicity could be measured by left ventricular ejection fraction (LVEF), which directly shows the pumping ability of the heart (Florescu, Cinteza, & Vinereanu, 2013). For hepatotoxicity, clinical criteria of chemotherapy‐induced hepatotoxicity is regularly defined by the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), alkaline phosphatase (ALP), and http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1392 (γ‐GT) in which increases to 2 or 3 times higher than the normal upper limit, as acute liver injury is occurring (Y. C. Yu et al., 2017). Nephrotoxicity is defined by serum creatinine level and GFRs (measured by urine volume produced in particular time period) and has five stages from risk to end‐stage renal disease (ESRD; Horie et al., 2018). The criteria of biochemical examinations could guide oncologists and researchers to monitor possible toxicities, which can be used to determine the benefits of anticancer efficacy and, subsequently, to proceed or to cease treatment. In practice, a physician could take a more restricted posture towards advancement of ALT and AST levels based on normal ranges, to securely assure the ongoing therapy. Likewise, the above criteria could be applied to monitor the chronic toxicity in liver, heart, and kidney which potent natural compounds/conventional drugs combination could provide greater anticancer efficacy without exceeding about criteria.

Prospectively, the immunostimulatory effect of natural compounds in chemotherapy is a critical issue, as chemotherapy‐induced immunosuppression could cause severe opportunistic infections (Galluzzi, Buqué, Kepp, Zitvogel, & Kroemer, 2015). Some natural compounds and herbal products have proved as immunomodulators in vivo, such as Ashwagangha (Withania somnifera) and Brahmi (Bacopa monnieri), which improve https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4968 and https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4985 expression after LPS exposure (Yamada, Hung, Park, Park, & Lim, 2011). Moreover, the immunomodulating activity of astragaloside (the major components of huang‐qi, Astragalus membranaceus) has been linked to http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1852 modulation that is essential for T‐cell activation (Qi, Gao, Hou, & Wan, 2017; Rheinlander, Schraven, & Bommhardt, 2018; Wan et al., 2013). Combining the immunostimulatory efficacy of herbal products with immunosuppressive chemotherapeutic drugs like gemcitabine, the side effects of immunosuppression might be relieved. Furthermore, these two studies propose a new approach for appraising the enhancement of the potential of natural compounds in combination with chemotherapeutic drugs. Before applying folk, herb, and natural compounds in combination therapy, the antitumor efficacy of folk, herb, and natural compounds needs to be assessed first.

4. CONCLUSION

Collectively, the mechanisms of natural compounds acting as chemotherapeutic adjuvants could be summarized into three approaches: directly potentiating tumoricidal effect (sensitizing cancer cells to be more responsive to chemotherapeutic drugs), reversing chemoresistance (diminishing drug efflux or overcoming other mechanism to increase the accumulation of chemotherapeutic drugs in cancer cells), and alleviating toxicity induced by chemotherapeutic drugs (promoting the repairing mechanism in normal cells against damage of chemotherapeutic drugs; Figure ​Figure2).2). After demonstrating anticancer activity as monotherapy, natural compounds could further enhance their application by being chemotherapeutic adjuvants or cooperating drugs in combination therapy. Using TCM or traditional herbal medicine as a chemotherapeutic adjuvant in treating NSCLC or gastric cancer could improve the quality of life of patients, ameliorate myelosuppression, and possibly reduce mortality (Hou et al., 2017; Y. K. Lee, Bae, Yoo, & Cho, 2018; X. Wu et al., 2016). Further studies should look at herbal compounds or low MW compounds that can be applied as an alternative potent supplement for cancer therapy to attenuate any adverse effects and chemoresistance. However, the toxicity of herbal–drug interactions for liver or kidney injury needs to be extensively considered as a precaution during new drug discovery and development.

Open in a separate window

Figure 2

Putative mechanism of natural compounds in chemotherapeutic synergism

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

Supporting information

Notes

Lin S‐R, Chang C‐H, Hsu C‐F, et al. Natural compounds as potential adjuvants to cancer therapy: Preclinical evidence. Br J Pharmacol. 2020;177:1409–1423. 10.1111/bph.14816 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Shian‐Ren Lin and Chia‐Hsiang Chang contribute equally in this study.

REFERENCES