Cancer is often either intrinsically resistant to chemotherapy drugs or develops resistance to them during the course of treatment. This is called chemoresistance, and accounts for up to 90% of all drug failures in metastatic cancers (cancers that have spread) (Abdullah 2013; Boyland 1963; Martinez-Rivera 2012; CCS 2014; Shen 2012; Hendlisz 2013). Chemoresistance occurs when cancer cells have or develop the ability to tolerate exposure to one or more chemotherapy drugs. Several inherent factors within tumor cells and the surrounding tumor microenvironment in the body contribute to chemoresistance, as dose suboptimal chemotherapy dosing (Abdullah 2013; Martinez-Rivera 2012; Wang, Chen 2016; CCS 2014).
Natural Agents to Combat Chemoresistance
Natural compounds exhibit a number of interactions with cancer cells that may enhance the anticancer cytotoxicity of chemotherapeutic agents. Cancer cells have highly developed mechanisms to rid themselves of toxins and degrade cytotoxic agents, including chemotherapy drugs. One key mechanism by which cancer cells eliminate toxins depends upon a protein called P-glycoprotein. This cell-membrane protein, which occurs in high amounts on cancer cells, pumps chemotherapeutic agents out of cancer cells. It is one of the chief culprits in multi-drug resistant cancer. Several natural compounds, such as quercetin, epigallocatechin-3-gallate (EGCG) from green tea, genistein, and curcumin inhibit P-glycoprotein (Abdallah 2015; Bansal 2009; Boumendjel 2011).
Another way that natural compounds may improve the cytotoxicity of chemotherapeutic agents is by preventing the metabolism of an active drug into inactive compounds. This problem is a particular concern for paclitaxel, which is readily broken down into inactive metabolites in the liver. Certain natural compounds, including the polyphenols fisetin and quercetin, may prevent this degradation. In a preclinical model of human liver metabolism, fisetin and quercetin inhibited the metabolic inactivation of paclitaxel (Vaclavikova 2003; Gustafson 2005).
Some unexpected and compelling findings about chemotherapy effectiveness were published in the journal Science in 2013. In this study, researchers used an animal model of cancer to establish the potential role of the ecosystem of the digestive tract, called the gut microbiome, in determining whether chemotherapy will be effective. Antibiotic-treated “germ-free” mice with cancer exhibited a poor response to immunotherapy and chemotherapy. Interestingly, the mice lacking normal microbiota showed low cytotoxicity and deficient free radical production in response to platinum chemotherapy. The authors stated, “optimal responses to cancer therapy require an intact commensal microbiota… These findings underscore the importance of the microbiota in the outcome of disease treatment.” (Iida 2013; Nelson 2015).
Numerous natural products have demonstrated potential as chemosensitizing agents, including (Shen 2012; Davenport 2010; Wesolowska 2011; Michalak 2012; Vinod 2013; Kim, Shin 2014; Sugiyama 2003):
Curcumin. Curcumin, a phytochemical derived from the spice turmeric (Somasundaram 2002; Saleh 2012), was shown to increase the effectiveness of various chemotherapeutic agents in laboratory and preclinical models of several types of cancer (Mitchell 2003). For instance, curcumin enhanced the effectiveness and decreased the toxicity of the antitumor antibiotics mitomycin-C and doxorubicin (Adriamycin) in cell and animal studies of breast and lung cancer (Wang, Shen 2013; Zhou 2009; Zhou, Wang, Liu, Zhang, Lu, Huang, 2011; Zhou, Wang, Liu, Zhang, Lu, Su 2011; Zhou 2014). A study in drug-resistant colon cancer cells found that curcumin enhanced chemosensitivity to 5-fluorouracil (5-FU) (Shakibaei 2014). Curcumin increased sensitivity to paclitaxel in cell culture and animals models of cervical cancer, and enhanced the antitumor effects of cisplatin (Platinol) in laryngeal carcinoma stem cells (Bava 2011; Sreekanth 2011; Zhang 2013). Furthermore, curcumin has demonstrated anticancer effects of its own, and may therefore be useful as an adjunct to conventional cancer treatment (Teiten 2010).
Poor oral bioavailability of many curcumin preparations might prevent adequate serum and cellular concentrations from being reached (Sunagawa 2015; Antony 2008; Chaurasia 2015; Sasaki 2011; Belcaro 2014; Catania 2013; Huang 2014).
Fortunately, BCM-95, a form of curcumin shown to have enhanced bioavailability (Antony 2008), may address this concern. One study showed that BCM-95 sensitized tumor cells to 5-FU and led to suppression of tumor growth. The authors first conducted a study using two 5-FU-resistant colorectal cancer cell lines. Treatment with BCM-95 curcumin and 5-FU showed synergism, with increased sensitivity and apoptosis compared with treatment with the drug alone. The second part of the study was conducted on mice that were transplanted with a 5-FU-resistant colorectal cancer cell line. These mice were injected intraperitoneally with 5-FU with or without 50 mg/kg of BCM-95 daily for 40 days. The 5-FU plus BCM-95 group showed greater inhibition of tumor growth compared with the 5-FU alone or control groups (Toden 2015).
Green tea. Multiple studies have shown the green tea constituents EGCG and theanine have antitumor activity and can enhance the anticancer effect of chemotherapeutic agents. In one study, the chemotherapy agent doxorubicin caused twice the tumor growth inhibition in mice given a green tea beverage compared with those that did not receive green tea. However, green tea did not increase doxorubicin uptake by normal tissue in the mice (Sadzuka 1998). Studies in mice with ovarian tumors showed that theanine plus doxorubicin was more effective in suppressing liver metastasis than doxorubicin alone. Theanine also enhances the antitumor effects of pirarubicin, irinotecan (Camptosar), and cisplatin (Sugiyama 2003; Sugiyama 1999).
Quercetin. In laboratory research, the flavonoid quercetin improved the sensitivity of several ovarian cancer cell lines to cisplatin and paclitaxel (Maciejczyk 2013). Quercetin plus cisplatin worked synergistically to suppress the growth of cultured hepatocellular carcinoma cells (Zhao 2014), and quercetin enhanced the ability of 5-FU to inhibit cell growth and stimulate apoptosis in esophageal cancer cells (Chuang-Xin 2012). In an oral cancer cell line, quercetin induced apoptosis and reversed drug resistance to vincristine (Oncovin) (Yuan 2015). An animal model of breast cancer found that a liposomal combination of vincristine and quercetin enhanced antitumor activity in tumors resistant to trastuzumab (Herceptin) (Wong 2011).
Omega-3 polyunsaturated fatty acids. The marine omega-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may have a role in cancer treatment alongside chemotherapy and radiation therapy (Calviello 2009; Shaikh 2010). In a clinical trial on 46 patients with non-small cell lung cancer, one group received chemotherapy alone (carboplatin [Paraplatin] plus vinorelbine [Navelbine] or gemcitabine [Gemzar]) and the other group received chemotherapy plus 2.5 grams of fish oil daily. The response rate in the chemotherapy and fish oil group was approximately two-fold greater compared with the chemotherapy-alone group. Patients in the fish oil group were able to undergo an average of one more cycle of treatment than those receiving chemotherapy alone. It is also important to note that the increase in efficacy of the drug regimen did not correlate with any increase in toxicity to healthy tissues (Murphy 2011).
In another clinical trial, patients with advanced breast cancer received cyclophosphamide, 5-FU, and epirubicin (Ellence) along with a DHA supplement. Twenty-five patients took 1.8 grams DHA daily for 7–10 days prior to chemotherapy and during five months of chemotherapy. At the end of the trial, the patients whose plasma DHA levels increased the most with supplementation had significantly better median survival and longer time to disease progression. For patients whose DHA levels increased the most, median overall survival was 34 months versus 18 months in participants whose DHA levels increased the least. Time to progession was also greater in those with more pronounced increases in DHA levels: 8.7 months versus 3.5 months. The researchers concluded that DHA can chemosensitize tumors (Bougnoux 2009). Support for this notion is provided by a laboratory study in which fish oil sensitized colon cancer cells to 5-FU, oxaliplatin (Eloxatin), and irinotecan (Granci 2013).
Melatonin. Comprehensive reviews of published scientific literature have found that melatonin, a hormone involved in the sleep-wake cycle, can increase tumor remission and one-year survival rates and alleviate chemotherapy and radiotherapy side effects in patients with a wide array of cancers (Wang 2012; Seely 2012). For instance, a meta-analysis of eight randomized controlled trials on individuals with solid tumor cancers found that melatonin supplementation increased the one-year survival rate from 28% to 52% when added as an adjuvant to chemotherapy or radiotherapy (Wang 2012). These studies typically used 20 mg of melatonin daily.
Protein-bound polysaccharide K (PSK). Protein-bound polysaccharide K (PSK) is a constituent of the mushroom Coriolus versicolor. Its anticancer and chemotherapy-enhancing properties have been studied extensively in Japan. Clinical trials have shown that, when used with standard treatment, PSK can significantly prolong survival in patients with various cancers including gastric, esophageal, colorectal, breast, and lung cancers (Maehara 2012; Fisher 2002; Kidd 2000). The dose of PSK used in the majority of studies was three grams daily.
Vitamin C. A 2013 study on ovarian cancer cells found that high concentrations of vitamin C (ascorbic acid or ascorbate) activated several anticancer mechanisms (Ohno 2009; Park 2013). A clinical phase of this same study was carried out on 22 patients with newly diagnosed Stage III or IV ovarian cancer. Ten participants received high-dose intravenous ascorbate (75–100 grams per treatment) along with standard chemotherapy (paclitaxel and carboplatin) for six months. Then, they continued the vitamin C alone for another six months. A separate group of 12 participants received six months of standard chemotherapy alone. Those treated with the vitamin C had chemosensitivity and reduced chemotherapy-associated toxicity. In addition, the median time to disease progression or relapse was 8.75 months longer in the vitamin C plus chemotherapy group (Ma 2014).
A 2015 clinical study on 14 patients with advanced cancer found that combining high-dose intravenous vitamin C with chemotherapy was safe and well tolerated. In fact, three patients with different types of cancer had unexpected temporary disease stabilization, reported increased energy levels, and experienced functional improvement (Hoffer 2015).
Other agents. The well-known Asian herb Panax ginseng enhanced chemosensitivity to several chemotherapeutic drugs, including 5-FU, irinotecan, mitomycin-C, docetaxel, cisplatin, and doxorubicin in laboratory and animal studies (Chen 2014; Kim, Jung 2014). Several other natural agents may enhance chemosensitivity as well, including gamma-tocotrienol, a form of vitamin E (Rajendran 2011), and the amino acid taurine, which increased the antitumor activity of doxorubicin in mouse sarcoma cells (Sadzuka 2009). In addition, preclinical studies found that vitamin D works synergistically with multiple chemotherapy regimens (Ma 2010).
Metformin Enhances Chemosensitivity
Metformin (Glucophage), a first-line drug for treating type 2 diabetes, may reduce the risk of several types of cancer and cancer-related mortality, and improve the response to some types of chemotherapy (Chae 2016; Daugan 2016; Lee, Kim 2012; Jiralerspong 2009). In an observational study, more diabetic patients taking metformin during neoadjuvant chemotherapy for early-stage breast cancer experienced pathologic complete responses than those not taking metformin. “Pathologic complete response” was defined as no evidence of invasive cancer in the breast or axillary (armpit) lymph nodes at the time of surgery (Jiralerspong 2009). Another observational study found that metformin use in diabetic cancer patients was associated with less frequent tumor recurrence after surgery (Lee, Kim 2012).
A 2013 study of esophageal cancer patients receiving chemotherapy and radiation before surgery found that diabetics taking metformin had a significantly higher rate of complete response to treatment than those not taking emtformin. In addition, the response was dose-dependent, meaning a higher dose of metformin was more effective than a lower dose. In a follow-up laboratory study, researchers showed that metformin sensitized esophageal cancer cells to 5-FU (Skinner 2013; Honjo 2014). In a study of patients with diabetes and advanced non-small cell lung cancer receiving first-line chemotherapy, those taking metformin had significantly less cancer progression and significantly longer survival (20 months) compared with those taking insulin or other diabetes medications (13 months) (Tan 2011).
Numerous laboratory studies have shown that metformin enhances the sensitivity of many different types of cancer cells to chemotherapeutic agents. One laboratory study found that metformin increased the chemosensitivity of throat cancer cells to cisplatin and paclitaxel (Zhang 2014). Another laboratory study found metformin increased the anticancer effects of the chemotherapy drugs doxorubicin and cisplatin in thyroid cancer cells (Chen 2012). Metformin also enhanced the sensitivity of endometrial cells to cisplatin and paclitaxel (Dong 2012). When combined with doxorubicin, metformin killed both breast cancer cells and breast cancer stem cells in culture (Hirsch 2009). A laboratory study found metformin increased the response to temozolomide (Temodar) in six out of eight chemotherapy-resistant tumor cell cultures taken from patients with newly diagnosed high-grade glioma, a type of brain cancer (Soritau 2011).
In addition, metformin may have a specific effect on residual cells remaining after chemotherapy treatment. In a mouse study, metformin significantly suppressed the regrowth of lung tumor cells after effective treatment with gefitinib (Iressa) (Kitazono 2013).