Liver cancer treatment natural

Alternative Therapies for Liver Cancer

Research on the use of complementary and alternative medicine for liver cancer is limited. But studies suggest that certain alternative therapies may offer benefits for people being treated for all types of cancer, including liver cancer. Some alternative treatments have been found to alleviate unwanted side effects of conventional cancer treatments, such as nausea and vomiting.

Compared with other types of cancer, liver cancer occurs relatively infrequently in the United States and Europe. That’s one reason why research on the use of complementary medicine and alternative medicine for liver cancer is sparse in Western countries. Studies on liver disease in general, however, are beginning to shed light on the potential ways complementary and alternative treatments might be used for liver cancer.

Liver Cancer: Complementary and Alternative Treatments

Much of the research on alternative medicine for cancer has examined the therapies’ ability to alleviate side effects of conventional treatments. Here are some of the latest ideas on the uses of complementary and alternative medicine for people with liver cancer:

  • Acupuncture. Studies have shown that acupuncture can help with nausea and vomiting among people with cancer. Nausea is a common side effect of chemotherapy, and nausea can be especially problematic for people with liver cancer. In addition to nausea caused by chemotherapy, “liver cancer patients can experience nausea related to the cancer itself because of where it is located,” explains Patrick Mansky, MD, medical oncologist and medical director for clinical research at the Cancer Team at Bellin Health in Green Bay, Wis.
  • Herbs. Milk thistle, a Mediterranean herb, has been used for centuries to treat liver problems. “Research is currently being done on milk thistle’s effect on liver toxicity from chemotherapy,” says Dr. Mansky. “That research may be relevant for liver cancer.” Mistletoe is another herb that is getting attention from liver cancer researchers. Recently, a small study in Egypt looked at the effects of mistletoe on liver cancer patients. Results from that study were quite promising, says Mansky.
  • Exercise. Yoga and tai chi may help patients overcome the fatigue that is commonly associated with liver cancer. “You have to be careful that you can tolerate certain positions,” Mansky points out, “but as long as it’s done under the supervision of an experienced teacher, it can be helpful.”
  • Diet. A healthy diet is essential for all cancer patients, but it is especially important for those with liver cancer. “The liver is one of the main organs in the digestive process,” explains Mansky. “If liver function is decreased, you have a more difficult time with digestion.” A diet rich in whole grains, fresh fruits and vegetables, especially green, leafy ones, can help promote digestion.
  • Massage. Liver cancer patients can sometimes experience edema, swelling that occurs when fluids build up in the body. In people with liver cancer, edema tends to affect the legs, ankles, and feet. Massage, when administered by a licensed, experienced massage therapist, who is knowledgeable about treating cancer patients, can help to relieve swelling. “There are no specific data on liver cancer,” says Mansky, “but there are some data on breast cancer patients whose arm swelling was decreased from massage.”

Liver Cancer: Be Careful With Herbal Therapies

Some herbal preparations, such as those mentioned above, may be helpful in treating symptoms associated with liver cancer. Even so, people who have liver cancer need to take extra precautions before taking an herbal remedy.

“A liver that is affected by cancer may have a harder time breaking down and metabolizing” substances, explains Mansky — in particular, alcohol. A person with cancer of the liver may have a harder time processing alcohol than people without liver disease and should avoid alcohol-containing products. Since many herbal preparations in extract form are alcohol-based, people with liver cancer should always check the ingredients for the presence of any alcohol before taking these herbs.

Additionally, some herbal supplements, such as gingko biloba, can cause excess bleeding. Because the liver releases important substances that help the blood to clot, liver cancer can decrease the body’s ability to stave off bleeding. As a result, people with liver cancer should discuss any new medications, including herbal supplements, with their doctor before taking them.

Could this vitamin A derivative cure liver cancer?

A new study reveals how a derivative of vitamin A called acyclic retinoid could help to eradicate the most common form of liver cancer: hepatocellular carcinoma.

Share on PinterestResearchers shed light on how a synthetic form of vitamin A could help to eradicate liver cancer.

Led by researchers from the RIKEN Center for Integrative Medical Sciences in Japan, the study found that acyclic retinoid blocks the expression of a gene that gives rise to liver cancer tumors.

Study leader Soichi Kojima, of the Micro-Signaling Regulation Technology Unit at the RIKEN Center, and colleagues recently reported their findings in the Proceedings of the National Academy of Sciences.

Around 22,000 men and 9,000 women in the United States are diagnosed with liver cancer every year.

The most common type of liver cancer is hepatocellular carcinoma (HCC). This cancer may begin as a single liver tumor that gets bigger over time, or it can start as multiple cancer nodules throughout the liver.

The biggest risk factor for liver cancer is infection with hepatitis B or hepatitis C; these viruses can lead to liver cirrhosis, which can cause cell damage that gives rise to cancer.

Previous research has found that acyclic retinoid — which is a synthetic derivative of vitamin A — has the potential to stop the recurrence of HCC in individuals who have undergone surgical removal of primary tumors.

The precise mechanisms underlying this association, however, have been unclear.

Acyclic retinoid reduces MYCN expression

To learn more about how acyclic retinoid might prevent HCC, the researchers investigated how the compound affects the transcriptome of cells, or the collection of RNA molecules that regulate gene expression.

The scientists found that, compared with untreated cells, cells exposed to acyclic retinoid showed a reduction in the expression of a gene called MYCN. This gene has been linked to the development of cancers such as neuroblastoma.

The researchers then suppressed MYCN gene expression in cancer cells. This not only halted cell proliferation, slowed cell-cycle progression, and stopped colony formation, but it also triggered cancer cell death.

Next, Kojima and colleagues took their investigation to cancer stem cells. Cancer stem cells are self-renewing cells that can drive the formation of tumors. As the researchers note, cancer stem cells manage to evade cancer treatments, so they are key players in cancer recurrence.

The team found that when MYCN gene expression was heightened in human HCC cell lines, this increased the expression of various markers that are linked to cancer stem cells, suggesting that MYCN gene expression is involved in HCC.

As Kojima explains, “The most interesting part of our finding is when we then looked at different subpopulations of heterogeneous cancer cells. We found one specific group of EpCAM-positive cancer stem cells, where MYCN was elevated.”

This spurred the team to investigate whether the anti-cancer effects of acyclic retinoid might be down to its effects on EpCAM-positive cancer stem cells.

A step closer to curing lung cancer?

When the researchers exposed HCC cancer stem cells to acyclic retinoid, they discovered that the compound selectively targeted and destroyed cells that were EpCAM-positive — the higher the dose of acyclic retinoid, the greater the effects on EpCAM-positive cancer stem cells.

Kojima and his colleagues then took liver biopsies of 12 people with HCC whose cancer had been eradicated following liver resection or ablation.

Six of these patients had received 600 milligrams of acyclic retinoid per day for 8 weeks, while the remaining six received 300 milligrams of the compound each day for 8 weeks.

The researchers found that the biopsies taken from patients who took the higher dose of acyclic retinoid showed lower MYCN expression.

Taken together, these findings indicate that acyclic retinoid could prevent HCC recurrence by reducing MYCN expression in EpCAM-positive cancer stem cells.

“It is remarkable that the acyclic retinoid clearly targets a certain category of cancer stem cells, and this provides us with important hints for decreasing cancer recurrence and truly curing patients.”

Soichi Kojima

The researchers note that acyclic retinoid is currently being tested in a phase III clinical trial for its ability to stop the recurrence of HCC.

What Chinese Medicine Can Do for Liver Cancer?

2.1. Single compounds from Chinese medicine for the treatment of liver cancer

Berberine is a natural product in many Chinese medicinal herbs, especially Coptidis rhizoma, which has been extensively studied and reported to show the antitumor action mostly by modulation of a number of different signal transductions. Currently, scholars have explored the antitumor action of berberine in liver cancer by various different strategies. For instance, in our laboratory, we found that berberine-induced cell death and tumor growth inhibition in xenograft model were demonstrated and mechanism was revealed that miR-23a might play a mediated role in berberine-suppressing HCC growth . Also, cyclin D1 overexpression is mainly responsible for tumor expansion, metastasis as well as angiogenesis. Berberine was found to repress the expression of cyclin D1 via proteasomal degradation in HCC . In addition, our group identified that berberine exerted antimigratory and anti-invasive abilities in HCC cells involving the upregulation of PAI-1 and downregulation of uPA . On the other hand, our group described for the first time that berberine could trigger autophagic cell death, in which the compound was shown to activate Beclin-1 and suppress mTOR . Actually, lung metastases in liver cancer are also a serious problem for patients, and we identified that the anti-invasive and antiproliferative actions of berberine in liver cancer was at least in part involved in the downregulation of Id-1, revealing a new anti-invasive mechanism . Hence, berberine is predicted as a new and potent natural molecule targeting liver cancer.

Flavonoids commonly exist in Chinese medicine and could be isolated from many different kinds of herbal medicine. In recent years, the precise molecular mechanism underlying the obvious antiliver tumor effect of flavonoids has been studied. For example, hydroxysafflor yellow A (HSYA), a kind of flavonoid extracted from Carthamus tinctorius L. owns the ability of antitumor. It was demonstrated that HSYA could result in angiogenesis inhibition of HCC by blocking signaling pathways of ERK/MAPK and NF-κB in comparison with negative control group. More interestingly, spleen and thymus indexes have been demonstrated to be improved, suggesting improvement on the immune system by HSYA . Oroxin B (OB) is one of the flavonoids isolated from Oroxylum indicum (L.) Vent. Li et al. investigated the antitumor effects of OB on HCC cell line SMMC-772 and studied the underlying mechanisms by which OB markedly inhibited expansion and induced apoptosis of the HCC cells. The antitumor activity of OB probably involved the inhibition of COX-2/VEGF and PTEN/PI3K/AKT signaling pathways, providing evidence for OB being used as a new therapeutic agent for liver cancer . Another flavonoid, namely luteolin, showed antineoplastic activity in a number of cancer cells. In SMMC-7721 HCC cells, luteolin induced apoptosis partially via modulation of autophagy, indicating luteolin serving as a regulator of autophagy in treating liver cancer .

Brucein D (BD) is an active constituent derived from Brucea javanica fruit, which has been employed as an antitumor recipe in Chinese medical practice. It was revealed that BD exerted observable apoptotic induction in HCC in vitro and in vivo, which was attributed to the reduced expression of miR-95 .

Matrine, a chemical component came from the roots of sophora species, mainly Sophora flavescens Ait (SF), has been used clinically to treat diseases such as liver fibrosis. The hepato-specific miR-122a has been found decreased in HCC cell lines . Zhou et al. reported that in HepG2 cells, matrine could cause cell arrest alteration as well as apoptosis induction with recovering expression of miR-122a . Actually, matrine is the prominent bioactive compound in one adjuvant treatment of liver cancer, namely Fufang Kushen injection, which was approved by Chinese FDA in 1995. Matrine has been deemed as the favorable lead source for drug discovery owing to its changeable structure and stable safety profile. Researchers designed and synthesized a group of matrine derivatives, which improved the antitumor activities of matrine in several human cancer cell lines. Among four tested cell lines, HCC cell line Bel-7402 responded more sensitively to compounds than the other three cell lines. Matrine and its derivatives induced G1 cell cycle blockage as well as migration inhibition in HCC cells . Another matrine derivative named WM622 showed remarkable inhibitory effect on HCC both in vivo and in vitro. Further study showed the apoptotic induction, cell cycle blocking in G0/G1 phase and the inhibition of PI3K/AKT signaling were involved in the antiliver cancer effect of WM622 .

Longikaurin A (LK-A) is a naturally occurring compound of ent-kaurane obtained from I. aternifolius. Researchers explored LK-A administration in liver of tumor-bearing mice models and discovered that LK-A could induce cell cycle arrest at G2/M phase with downregulation of Skp2 and subsequently resulted in induction of ROS/JNK/c-Jun apoptotic pathway in HCC cells .

The antitumor of two known pennogenyl saponins, which are derived from R. paridis axialis, was investigated in orthotopic nude-mouse model. The data indicated that these two monomers dose dependently suppressed the HCC progression through activating both caspase-independent and caspase-dependent apoptotic pathways. Furthermore, possible mechanism probably involved the modulation of mitogen-related protein kinase pathway as well as the suppression of PI3K/Akt signaling .

Isoquercitrin was found to strongly repress liver tumor cells via retarding the G1 phase cell cycle and promoting cancer cells apoptosis. In nude mice, the proliferation of transplanted tumors was suppressed after treatment with isoquercitrin. Further study showed that the underlying mechanism might be closely involved in the MAPK and PKC signaling pathways .

Zhang et al. investigated the effect of astragaloside IV (AS-IV) and curcumin on tumor expansion and angiogenesis in nude mice bearing xenografts of HCC. Combining AS-IV and curcumin revealed significant synergistic repressive efficacy against both angiogenic and thrombosis-related factors, which might be mediated by downregulation of miR-221 as well as upregulation of miR-122. This current study indicated future clinical potential of combination therapy with AS-IV and curcumin for treatment of liver cancer .

Ursolic acid (UA), a naturally occurring pentacyclic triterpenoid carboxylic acid found among Chinese herbal medicine, has been reported to be a potent component for cancer prevention, including liver cancer. Yie et al. explored the probable mechanisms underlying the antiliver cancer action of UA. Taken together, the results demonstrated that UA inhibited proliferation and induced apoptosis of HCC cells via AMPKα-mediated suppression of Sp1, followed by suppressing DNMT1 expression. The investigation revealed a potential novel mechanism by which UA controlled proliferation of HCC cells, suggesting the critical effect of DNMT1 in HCC chemoprevention and treatment .

Bilobol is a Chinese medical ingredient. Xu et al. identified that bilobol administration could suppress expansion of HepG2 cells, which pretreated with lipopolysaccharide (LPS) to induce inflammation. Bilobol appeared to exhibit antitumor effect via inhibiting the RhoA/ROCK signal transduction during the anti-inflammatory response .

Fucoidan, a sulfated polysaccharide isolated from brown algae, has been applied as an anticancer drug for hundreds of years in Chinese medicine. The results from Zhu et al. revealed that fucoidan had the capacity of antitumor partially through inhibiting the proliferation of HCC cells, although it is unable to repress the angiogenesis induced by HCC . In another study, fucoidan displayed the antimetastatic efficacy on HCC cell lines via upregulating p42/44 MAPK-dependent NDRG-1/CAP43 pathway. Also, fucoidan was found to protect against bile acid-induced hepatocyte apoptosis. This ability suggested fucoidan presented a potent therapeutic agent for HCC treatment .

Telekin is a eudesmane-type sesquiterpene lactone extracted from the natural plant Carpesium divaricatum, which presents strong antiproliferative activity in cancer cells. Zheng et al. found that telekin promoted HCC cells apoptosis by activating the mitochondria-mediated apoptotic pathway .

Gigantol is a phenolic substance derived from the genus Dendrobium. Chen et al. investigated gigantol efficacy on liver cancer cells and the results suggested gigantol inhibited cells expansion and induced apoptosis in HepG2 cells through PI3K/Akt/NF-kappaB signal transduction .

The endoplasmic reticulum (ER) stress and unfolded protein response (UPR) play critical roles in the modulation of cell fate. The two factors even could become potent targets and provide support for the development of antineoplastic agents. Celastrol, one of the triterpene compounds derived from herbal medicine, exerts antitumor effects on various malignancies. Ren et al. demonstrated that for HCC cells, exposure to celastrol led to the sensitivity of the intrinsic apoptotic pathway, at least partly through ER stress and the UPR. Moreover, celastrol was found to repress H22 tumor growth in murine syngeneic model studies by inducing ER stress and apoptosis. These data suggested that targeting ER-stress/UPR was an efficient way for celastrol becoming a potent drug for HCC therapy . Cytisine, a quinolizidine alkaloid, also a major bioactive constituent purified from the Sophora alopecuroides L. It was reported to exhibit inhibitory effects in treating liver cancer by inducing the ER stress-mediated apoptotic pathway through activating CHOP, JNK, and caspase-4 signaling pathways in liver cancer cells. This phenomenon suggested a novel target compound potentially to treat liver cancer .

RA-XII, a naturally occurring compound originated from Chinese herbal medicine Rubia yunnanensis, possesses activities of anti-inflammatory and antitumor. Song et al. revealed that RA-XII accelerated apoptosis and repressed protective autophagy via signaling pathway AMPK/mTOR/P70S6K in HepG2 cells, suggesting RA-XII, a cyclopeptide, provides the therapeutic support for potentially being an autophagy inhibitor drug in the therapy of hepatic tumor .

There are many bioactive compounds from Chinese medicine, which are also one part of daily diet. For example, Bullacta exarata is widely used as a part of normal diet in Asia, and also it is an agent with liver- and kidney-nourishing functions. One polysaccharide conjugate BEPS-IA was extracted from B. exarata. Liao et al. reported that BEPS-IA exerted a potent inhibition in HepG2 cells growth in a concentration-dependent manner via inducing apoptosis and blocking cell cycle. Furthermore, it was corroborated that this effect was involved in downregulation of Bcl-2, upregulation of p53, p21 and Bax, suggesting that BEPS-IA may be a new dietary drug for HCC obtained from herbals and shed light on getting a deeper understanding on the action mechanisms . Diosgenin is a major bioactive component of Dioscoreaceae plants including yam, which is commonly prescribed in Chinese medicine, and a common vegetable all over the world. Diosgenin remarkably repressed the proliferation of several HCC cell lines in a dosage-dependent manner. Deeper investigation reported the apoptosis and cell cycle G2/M arrest were involved in the inactivation of Akt, activation of the caspase cascades, and upregulation of p21 and p27 expression. These results suggested that diosgenin may serve potentially as a novel antiliver cancer dietary supplement . Armillaria mellea (A. mellea) is a honey mushroom, which is currently often consumed worldwide as a dietary supplement. Armillarikin was purified from A. mellea, which is an important component of Chinese medicine “Tianma.” Chen et al. investigated the cytotoxicity of armillarikin against HCC cell lines such as Huh7, HA22T, and HepG2 cells. Armillarikin treatment induced apoptosis that was mediated by ROS and accompanied by the collapse of mitochondrial and activation of caspase-8 and -3 in cancer cells, suggesting the potential of armillarikin serving as an potent antihepatoma drug . Corosolic acid analogue (CAA) is a triterpenoid saponin isolated from Actinidia valvata Dunn (Actinidiaceae), a kind of well-known fruit. The study investigated the antiproliferation and inducing apoptosis effects of CAA in three hepatoma cell lines. The data showed for the first time that CAA inhibited expansion of liver cancer cell lines and induced G1 phase arrest. Moreover, proapoptotic effect of CAA was mediated by the activation of TNF-α, caspases, and mitochondrial pathway .

1,6,7-trihydroxyxanthone (THA) is an active small molecule purified from Goodyera oblongifolia. The compound was discovered to strongly inhibit cancer cell proliferation and induced apoptosis in hepatoma carcinoma cells partially mediated by the repression of Bmi-1 and activation of miR-218 .

An active ingredient cordycepin was extracted from “Dong Chong Xia Cao.” It has been implicated in regulating multiple physiological actions especially antitumor effects. Yao et al. revealed that cordycepin might contribute to tumor progression, EMT, migration, and invasion inhibition in HCC by suppression of signaling pathways E-cadherin and integrin/FAK. Hence, cordycepin is a supplementary candidate or therapeutic agent for preventing liver tumor expansion .

Norcantharidin (NCTD), a small-molecule antitumor drug originated from small animal blister beetle, has been currently applied as a potent antineoplastic agent for several kinds of cancers including HCC. The expression of FAM46C, which has been firstly reported as a tumor suppressor for multiple myeloma, was demonstrated to enhance with NCTD administration. FAM46C, a tumor inhibitor for HCC, was important for proapoptotic effects and antiproliferation of NCTD . Another study investigated the mechanism of NCTD-induced apoptosis in HepG2 cells, which indicated that NCTD could reverse the methylation state of RASSF1A gene and recover its expression, providing the theoretical information for further development in clinical application . Also, Zhang et al. found in multiple HCC cell lines that NCTD could induce transcriptional repression of Mcl-1 and significantly enhance ABT-737-triggered cell viability inhibition and apoptosis .

Bufalin is the major bioactive constituent of the Chinese medicine Chansu, which is presently employed in clinical practice for cancer therapy. A number of groups have investigated the therapy efficacy of bufalin on hepatoma, either in vivo or in vitro, to explore the therapeutic potential of the drug. Qiu et al. reported that bufalin exhibited considerable antitumor activities in liver cancer cell lines HCCLM3 and HepG2 and the underlying mechanism might be related to the repression of signaling pathway AKT/GSK3β/β-catenin/E-cadherin . Tsai et al. demonstrated that bufalin led to autophagic cell death and G2/M cell cycle phase arrest in SK-HEP-1 HCC cells via activating AKT/mTOR signal transduction pathway . Another group reported that bufalin exerted remarkable antiproliferative activity and apoptosis induction in Huh-7 and HepG-2 cancer cells. Further study supported the prosurvival role of bufalin-induced autophagy when the autophagy pathway was retarded with specific chemical inhibitors, indicating a promising therapeutic approach for HCC therapy combining bufalin with a specific autophagy inhibitor .

In searching for active antihepatoma ingredients from toad venom, which is a frequent prescription applied in HCC treatment, Zhang et al. discovered that arenobufagin, a bufadienolide derived from toad venom, had prominent anticancer capacity against HepG2 cells and the corresponding multidrug-resistant cells, namely HepG2/ADM. They illuminated the molecular mechanisms of arenobufagin, which involved crosstalk between autophagy and apoptosis through PI3K/Akt/mTOR pathway suppression. Consequently, these findings contributed to the development of arenobufagin into a chemotherapeutic agent in liver cancer treatment . Another compound, namely hellebrigenin, which was also isolated from Venenum bufonis, was found to significantly repress HepG2 cell viability and colony formation. Further exploration revealed the cytotoxicity of hellebrigenin in HepG2 cells and underscored the antihepatoma activity of hellebrigenin as an active component of Venenum bufonis. Hellebrigenin induced DNA damage, triggered cell cycle arrest, and subsequently initiated mitochondrial apoptosis. Moreover, Akt was found to take a role in cell cycle and apoptosis modulation induced by hellebrigenin. The findings showed the potential of hellebrigenin used as a chemotherapeutic drug for future HCC clinical application .

What’s New in Liver Cancer Research?

Because there are only a few effective ways to prevent or treat liver cancer at this time, there is always a great deal of research going on in the area of liver cancer. Scientists are looking for causes and ways to prevent liver cancer, as well as ways to improve treatments.

Prevention

Some scientists believe that vaccinations and improved treatments for hepatitis could prevent about half of liver cancer cases worldwide. Researchers are studying ways to prevent or treat hepatitis infections before they cause liver cancers. Research into developing a vaccine to prevent hepatitis C is ongoing. Progress is also being made in treating chronic hepatitis.

Screening

Several new blood tests are being studied to see if they can detect liver cancer earlier than using AFP and ultrasound. Ones being studied include DCP, Glypican-3, osteopontin and Golgi protein-73. CT scans and MRI scans are also being studied as different imaging tests to screen for liver cancer instead of ultrasound.

Surgery

Newer techniques are being developed to make both partial hepatectomy and liver transplants safer and more effective.

Adding other treatments to surgery

An active area of research uses adjuvant therapies – treatments given right after surgery – to try to reduce the chances that the cancer will return. Most of the studies so far using chemotherapy or chemoembolization after surgery have not shown that they help people live longer. Research studies are also looking into newer drugs, like targeted therapy and may prove to be more effective. Some promising results have also been seen with radioembolization, but these need to be confirmed in larger studies. Another area studied has been the use of anti-viral therapy in people with liver cancer related to having viral hepatitis to see if it improves outcomes after surgery.

Doctors are also studying ways to make more liver cancers resectable by trying to shrink them before surgery. Studies are now looking at different types of neoadjuvant therapies (therapies given before surgery), including targeted therapy, chemotherapy, ablation, embolization, and radiation therapy. Early results have been promising but have only looked at small numbers of patients.

Determining recurrence risk after surgery

After a partial hepatectomy, one of the biggest concerns is that the cancer might come back (recur). Knowing someone’s risk for recurrence after surgery might give doctors a better idea of how best to follow up with them, and may someday help determine who needs additional treatment to lower this risk.

Researchers are studying ways to predict if the cancer will come back by testing the liver cells in the surgery sample through genetic profiling. These studies are promising but will need to be confirmed in other larger studies before it is widely used.

Ablation therapy

Newer ablation techniques are being studied. One type, called irreversible electroporation, is an ablation procedure that does not use heat or cold to destroy cancer cells. It uses high voltage to open the “pores” of the cell (like the pores of your skin) which causes the cancer cells to die. It may be very useful for cancers that are in difficult areas to treat, such as near blood vessels.

Targeted therapy

New drugs have been developed that work differently from standard chemotherapy drugs. These new targeted drugs act on specific proteins in cancer cells or their surrounding environments.

Tumor blood vessels are the target of several newer drugs. Liver tumors need new blood vessels to grow. The drug sorafenib (Nexavar), which is already used for some liver cancers that can’t be removed surgically, works in part by hindering new blood vessel growth. This drug is now being studied for use earlier in the course of the disease, such as after surgery or trans-arterial chemoembolization (TACE). Researchers are also studying whether combining it with chemotherapy may make it more effective.

Ramucirumab (Cyramza) is another targeted drug that works on blocking new blood vessel growth which can result in tumor shrinkage. It is already being used in other cancers such as stomach cancer, NSCLC and colorectal cancer. It is being studied in people with liver cancer with positive results.

Biomarkers

Knowing which liver cancers will respond to certain treatments before giving them would help save people from side effects of unhelpful drugs. Research is being done to look for specific biomarkers (proteins) such as p-ERK, or genomic profiling (specific gene changes of a cancer) to see if targeted therapy or immunotherapy can be chosen based a tumor’s special traits.

Virus therapy

A newer approach to treatment is the use of a virus, known as JX-594. This started as the same virus that was used to make the smallpox vaccine, but it has been altered in the lab so that it mainly infects cancer cells and not normal cells. A solution containing the virus is injected into liver cancers, and the virus can enter the cancer cells, where it causes them to die or to make proteins that result in them being attacked by the body’s immune system. Early results of this treatment against advanced liver cancer have been promising, even in patients who have already had other treatments.

Herbal Medicines in the Treatment of Liver Diseases – Efficacy, Action Mechanisms and Clinical Application

Liver diseases, including viral hepatitis, liver cirrhosis, liver cancer and so on, are common illnesses posing a serious threat to public health. At present, hundreds of millions of people are suffering from liver diseases around the world, which exert a negative impact on patients’ quality of life.
Herbal medicine has long been associated with the treatment of liver diseases in clinical settings, especially in East Asian countries (e.g. China, Japan, Mongolia). However, multi-target and multi-functional effects, among other factors, have made fundamental mechanistic insights and general pharmacological interactions difficult to elucidate and therefore, treatment efficacy is difficult to unambiguously define. This has implications for the safety profile of treatments, and the improper use of herbal medicine (e.g. Polygonum multiflorum, Radix bupleuri, Angelica archangelica, Scutellaria baicalensis) may increase the risk of liver disease progression, and lead to deterioration of patients’ condition.
However, herbal medicine has potential advantages in the treatment of liver diseases. It can be applied to patients with liver diseases in case conventional therapies exhibit poor curative efficacy and can also be taken as adjuvant treatment for liver cancer with surgery, radiotherapy and chemotherapy. Additionally, treatment by herbal medicine for medical withdrawal can be flexible and convenient, with small risk of withdrawal reactions and relative low costs. Thus, it is necessary to conduct in vivo, in vitro, and clinical studies on herbal treatment of liver diseases, which will provide scientific basis for the clinical application of herbal medicine in this field.
The aim of this Research Topic is to encourage researchers from all over the world to explore the pharmacology and clinical efficacy of herbal medicine in treating liver diseases through a rigorous profiling of pharmacologically-relevant ingredients, laying more emphasis on pharmacodynamics and mechanisms of action. We also welcome studies on the reasonable usage (e.g. dosage and duration) of herbal products to not only improve their curative effects on liver diseases but also reduce the risk of herb-induced liver injury, as well as identification of proper combination of herbal and conventional medicine, maximizing the clinical efficacy of drugs on liver diseases. Reviews which critically assess this topic are particularly welcome. Authors are reminded that also in view of the seriousness of these conditions, scientific rigour is of particular relevance and that the studies must be based on a clearly defined hypothesis or testable research question. ‘Negative’ outcome studies are equally welcome.
Manuscripts considered for publication in this Research Topic should focus on one or more of the following 3 broad areas:
1. Discovery of new herbal formula, single botanical drugs or plant-derived compounds with therapeutic effects on liver diseases.
Herbal medicine and its active constituents have been widely used as a potential treatment for liver disease in clinical practice (e.g. Compound glycyrrhizin tablets, Bicyclol tablets and Bifendate pills derived from herbal medicine). Further studies on the diversified ingredients of herbal products, single herb or herbal prescriptions will be beneficial for the discovery of novel drugs in the treatment of liver diseases. It should be noted that preparation, structural characterization and content determination of herb-derived compounds with therapeutic effects must be clearly illustrated in the manuscripts.
2. Exploration of interactive mechanisms of the combination of herbal and conventional medicine.
Clarifying negative or positive interactions and their mechanisms of herbal medicine and conventional medicine in the treatment of liver diseases is an essential topic in this context. Such studies will also lead to enhanced understanding and avoidance of negative outcomes – such as understanding the effects of herbal metabolites on drug-associated enzyme activity. Studies on this area must be based on pharmacologically relevant in vivo or cell based models. Simple in silico and pharmacologically irrelevant assays are not acceptable as a main tool for pharmacological assessment.
3. Studies on the reasonable usage (dosage and duration) of herbal medicine in the treatment of liver diseases.
Evaluating dosage and duration of herbal medicinal products for liver diseases, so as to improve the therapeutic effects of herbal medicine, and decrease the incidence of herb-induced liver injury.
The four pillars of best practice in ethnopharmacology
With these guidelines we define in detail what constitutes best practice for manuscripts submitted to Frontiers in Pharmacology; Section Ethnopharmacology. They provide a basis for the peer review and build on the general requirements of Frontiers in Pharmacology.
1) Pharmacology
a) The manuscript (MS) must report a substantive body of ethnopharmacological research, to be considered as an independent addition to the literature. In general, we expect that such studies are based on local / traditional uses of plants or other natural substances which need to be spelled out clearly.
b) For pharmacological studies, the model used must be one which is either generally accepted in the field as valid or a credible alternative whose general development, and application in the reported instance, has been justified.
Specifically antioxidant activity must be based on a pharmacologically relevant in vivo or cell based model. Simple in silico and pharmacologically irrelevant assays for antioxidant activity (e.g. the DPPH assay, FRAP (Ferric Reducing Ability of Plasma), ABTS (2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)) are not acceptable as a main tool for assessing an extract or a compound for activity.
c) Similarly, simple screening for anti-microbial effects of crude extracts is no longer state-of-the-art. Authors must follow the widely accepted standards for microbiological testing (cf. Cos et al. 2006 Anti-infective potential of natural products: How to develop a stronger in vitro ‘proof-of-concept’ Journal of Ethnopharmacology 106: 290–302) and subsequent methods papers. Such research is only meaningful if it contributes to our mechanistic understanding of anti-microbial effects, its specificity or identifies novel leads.
d) The dose ranges must be therapeutically relevant. While it will be impossible to define an exact cut-off, the literature in the field is now replete with studies which test extracts at implausibly high doses. Single dose studies will only be of relevance in exceptional circumstances (e.g. in case of specific complex pharmacological models). And of course, positive and negative controls must be included.
e) In order to establish therapeutic benefits, selectivity data are essential. How specific is the effect? Many compounds have non-selective in vitro effects and research on common compounds must be justified in terms of the potential therapeutic benefits. While such research may be relevant and have potential applications, authors will need to assess the specificity of a single compound or an extract rich in a well-studied compound (like rutin, curcumin, or quercitin) and provide evidence for the relevance and novelty of the approach
2) Composition:
a) Botanical:
The identification of the study material must be described well. All species are fully validated using Kew MPNS portal or The Plant List initiative or Plants of the World Online Of course, full botanical documentation is essential (i.e. a voucher specimen deposited in a recognised herbarium). A scan of the voucher(s) is welcome as supplementary material and encourage authors to include the coordinates of the location where the material had been collected.
b) Chemical
– The composition of the study material must be described in sufficient detail. Chromatograms with a characterisation of the dominating compound(s) are preferable. If preparations are used which are available commercially quality parameters provided in pharmacopoeia must be provided. The material under study must be characterised using the methods of the relevant monograph
– If ‘pure’ compounds are used sufficient information on the level of purity must be included. Especially in in vitro models, the authors must be confident that the compounds are stable under the conditions used (for example, they do not degrade due to high concentrations of DMSO). A critical aspect that should be considered is how these assays and extraction protocols are linked to local and traditional uses. In this way, variables such as the solubility of the compound in the traditional preparation and in the analytical extraction protocol should be taken into consideration
– All chemical line structures must be drawn using a internationally accepted structure drawing programme, must be consistent and – if possible and relevant – the stereochemistry needs to be given.
c) Multiherbal preparations:
Very often multiherbal preparations are used. Full information on their composition (in terms of the botanical drugs / species included) and information on the rationale for studying this preparation needs to be included. It is essential that in these cases sufficient details are provided on the botanical (2a) and chemical (2b) characterisation.
3) Basic requirements and research ethics
Frontiers has very well developed guidelines relating to ethical aspects of a MS. Specifically, for Frontiers in Pharmacology (Ethnopharmacology) the following key requirements are essential:
a) The objectives of the research reported must be spelled out clearly and in detail. All MS must critically assess the scientific basis of the work and provide meaningful conclusions, which are based on a clear hypothesis / research question as defined in the introduction. Ethnopharmacological research must assess whether a compound or plant extract has a certain effect and it cannot be about ‘confirming an extract’s or compound’s effects or efficacy’.
b) Research must add new and scientifically substantive knowledge to our understanding of the pharmacology and use of medicinal plants. A key basis for this is a review of literature relevant to the pharmacological activity already reported on the species including possibly related taxa or compounds. This must be up-to-date, and clearly demonstrate the substantive addition to the literature the MS submitted represents. Simply using advanced measurements/techniques/protocols reproducing previous studies of the same plant product will only be accepted in exceptional circumstances (e.g. previously unknown, highly active components are discovered).
c) Compliance with all international ethical standards is essential. In the context of ethnopharmacology, the Convention on Biological Diversity and, most recently, the Nagoya Protocol are of particular relevance (https://www.cbd.int/abs/).
d) Research in ethnopharmacology is based on local and traditional knowledge often passed on orally over generations. Ultimately, research in this field must therefore benefit those populations who are or were the original keeper of this knowledge.
e) The use of animals must be justified in the context of novelty (see also part 1). It is ethically not acceptable to have yet another in vivo study on an already well-studied species, demonstrating some common activity (e.g. an anti-inflammatory effect studied in the rat-paw edema). The same is true for species which are chemically very similar (and generally are rich in common ingredient) to ones already studied pharmacologically. Such studies must ‘meet(s) the standards of rigor’ we expect in ethnopharmacology as defined in the Frontiers’ guidelines.
4) Other specific requirements
a) Studies focusing on local and traditional uses of plants (ethnopharmacological field studies) must be based on substantial, original data. The relevance of the MS in the context of previous studies in the geographical region must be spelled out clearly and it must contribute to the understanding of the therapeutic uses of plant species and inform experimental or clinical studies This includes an adequate presentation and discussion of the data. Also, social science centered studies (e.g. ethnobotanical studies or health system research of local and traditional medical systems) are welcome. This journal subscribes to the ConSEFS standards including any updates.
b) In case of reviews, we expect clearly defined scientific aims (objectives), a comprehensive, critical and specific assessment of the relevant information linking local and other medical uses to the biomedical and bioscientific evidence. Reviews need to define future research needs and priorities. It is essential that the scientific quality of the original articles cited is assessed. If pharmacological studies are reviewed, particular attention must be paid to assessing the quality of the studies.
c) Food plants are commonly reported to have pharmacological effects. Frontiers in Ethnopharmacology focuses on therapeutic benefits of such species and not on the general food/nutritional properties.

Keywords: Herbal Medicine, Cholestatic Hepatitis, Efficacy, Action Mechanism, Clinical Application

Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

Liver cancer has always been a difficult diagnosis. And today, the number of people who develop liver cancer is increasing, making primary liver (and bile duct) cancer the fastest-rising cause of cancer-related death in the United States.

Experts attribute this to the high prevalence of fatty liver disease, a condition associated with insulin resistance, obesity, high blood pressure and high cholesterol levels.

The good news is we have newer treatments that are making a significant impact in helping patients with liver and bile duct cancers live longer and with a better quality of life. These new approaches include the latest immunotherapy drugs, a focus on making complicated liver surgery safer for more patients, and using embolization procedures in new ways and new combinations.

Immunotherapy for Liver Cancer

Immunotherapies stimulate the body’s immune system to recognize the cancer as an invader and attack it. Two of these latest drugs—nivolumab (Opdivo®) and pembrolizumab (Keytruda®)—have had success with other difficult cancers such as melanoma and non-small cell lung cancer. We are rapidly learning that these can be effective for primary liver cancer as well.

Nivolumab recently received accelerated FDA approval for patients with advanced liver cancer. (Nivolumab was the drug that former President Jimmy Carter took after his melanoma was found to have metastasized to both his brain and liver. Months later he announced he was cancer-free and needed no further treatment.) Pembrolizumab, initially approved for melanoma, recently received approval for any inoperable or metastatic solid tumor with certain genetic characteristics, regardless of disease site—a first for the FDA.

These represent a new class of drugs to use against liver cancer. Currently the only standard drug is sorafenib, a chemotherapy drug that inhibits certain enzymes in the cancer cells, causing them to break down and die off, at least for a little while. Unfortunately, it only extends survival by about three months and produces some harsh side effects. Clearly, we need better therapies.

Currently, we are using these new immunotherapy drugs in patients with metastatic liver cancer and in those who have a large burden of disease and cannot undergo surgery or a liver transplant. We hope to study these drugs in more trials, and in combination with other treatments such as radiation.

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Surgery for Patients with Cirrhosis

Most primary liver cancer occurs in patients with cirrhosis of the liver, a progressive liver disease in which scar tissue replaces healthy liver cells. Patients with cirrhosis typically are not able to undergo surgical treatment, because after tumors are removed, the remaining liver is still diseased, and the risk for liver failure is much higher. Safely operating on patients with cirrhosis is one of the procedures I brought to Roswell Park. We are able to take certain measures before and after surgery to help reduce the risk for liver failure. These involve a combination of approaches, including food management, medications and strict patient selection criteria. As a result, we’re able to extend the benefit of surgery to these patients, and do it safely.

Radioembolization

Radioembolization is a procedure that uses tiny glass or resin microspheres (beads) that contain radioactive material to combat liver cancer. When the spheres are injected into the artery leading to the tumor, they deliver radiation directly to the tumor itself. While this procedure does not usually cure the cancer, it does have good success in prolonging survival with very good quality of life. Roswell Park is a high-volume center for this procedure, and among the top 10 in the nation. We do about 80 transarterial radioembolization procedures a year. Survival with this procedure for patients with early- to mid-stage cancer is approaching three years. The procedure is also very well-tolerated and most patients go home the same day. Combining radioembolization with immunotherapy makes one of the safest treatment approaches for cancer.

These advances, even in just the past few years, have markedly prolonged survival and improved the quality of life for patients with primary liver and bile duct cancers.

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