Rice bran arabinoxylan compound as a natural product for cancer treatment – an evidence-based assessment of the effects and mechanisms

Figures & data

Figure 1. A Flow diagram of evidence selection.

Table 1. Results from human and animal studies on the immune restorative capacity of RBAC in cancer.

#	RBAC (dose)	Study Design	Key Findings	Reference
1	Biobran MGN-3 (3 g/day for 1 to 2 weeks)	Before & after study. Various malignancies (n = 32)	Biobran MGN-3 significantly increased (p < 0.001) NK cell cytolytic activity up to 10-fold compared to baseline. Increased NK cell granularity with enhanced tumor-killing capacity was observed post-treatment.	Ghoneum and Brown (1999)
2	Biobran MGN-3 (3 g/day for 1 month)	Before & after study. Various malignancies (n = 5)	Statistically significant (p < 0.001) increases in responses with T & B cell mitogen tests compared to baseline demonstrated signs of restoration of the adaptive immunity.	Ghoneum and Brown (1999)
3	Biobran MGN-3 (3 g/day for 1 to 2 weeks)	Before & after study. Various malignancies (n = 90)	95.5% of patients demonstrated 2 to 10-fold increases in NK cell cytolytic activity at 1–2 weeks post-treatment.	Ghoneum (1999)
4	Biobran MGN-3 (3 g/day for 18 months)	RCT. Patients with progressive cancer of late stages (n = 152, RBAC = 96, Control = 56).	A significantly higher portion of participants with low or medium NK cell activity in the RBAC group survived than the control group (Low: 42.5% vs. 12.5%, p < 0.01; Medium: 51.4% vs. 28.0%, p < 0.05).	Takahara and Sano (2004)
5	Biobran MGN-3 (2 g/day for 1st month, 1 g/day for 2^nd month)	Before & after study. Various malignancies (n = 22)	A statistically significant change in the ratio of Th/Treg was detected (p = 0.025), and the increase in Th/Treg was more pronounced in participants with low Th/Treg at baseline.	Lissoni et al. (2008)
6	Biobran MGN-3 (2 g/day for 3 months)	RCT. MM patients (n = 48, RBAC = 32, placebo = 12)	Significant increases in NK cell activity of the RBAC group compared to the baseline in the first (p = 0.045) and second (p = 0.029) months. The circulating mDC percentage (p = 0.036) and mDC/pDC ratio (p = 0.030) increased substantially after 3 months.	Cholujova et al. (2013)
7	Biobran MGN-3 (3 g/day for 4 weeks)	RCT. Cervical cancer patients (n = 14, RBAC = 7, placebo = 7)	Both groups experienced declines in NK cell activity after chemoradiotherapy compared to the baseline values, with no significant difference between the two groups.	Itoh et al. (2015)
8	Biobran MGN-3 (40 mg/kg BW p.o. every other day for 8 months)	Wistar rats + carcinogen (MNNG)	MNNG caused significant lymphocyte depletion (↓23.3%, p < 0.01) after 8 months compared to healthy controls. RBAC + MNNG promoted lymphocyte recovery to normal levels (p < 0.05).	Badr El-Din et al. (2016a)
9	Biobran MGN-3 (2 g/day for 6 months)	Before & after study. MGUS/SMM patients (n = 10)	Half of the patients had neutropenia at baseline. After consuming RBAC, eight participants showed an increased neutrophil count between 10 and 90%.	Golombick et al. (2016)

Abbreviations: BW: body weight; CD: cluster of differentiation; mDC: myeloid dendritic cells; MM: multiple myeloma; MNNG: methylnitronitrosoguanidine; NK: natural killer; p.o.: per oral; pDC: plasmacytoid dendritic cells; RBAC: rice bran arabinoxylan compound; RCT: randomized controlled trial; Th: T helper cells; Treg: regulatory T cells; MGUS/SMM: monoclonal gammopathy of undetermined significance/smoldering multiple myeloma.

Figure 2. The immune restorative effects of rice bran arabinoxylan compound (RBAC). (A) shows some immune functions that are affected by tumour growth resulting in the suppression of antitumor activity. (B) shows the biological response-modifying effects of RBAC restoring immune function in cancer patients.

Table 2. The in vivo anticancer effects of RBAC from murine models with tumour growth inhibition and life prolongation as outcome measures.

#	RBAC (dose)	Model	Key Findings	Reference
1	Biobran MGN-3 (1.5 mg/day p.o. for 23 days)	ICR mice + S-180 cells	TW ↓66.2% (0.51 ± 0.34g vs. 3.40 + 1.46g, p < 0.01) compared to the control. Better than PSP with TW ↓49.0% (p < 0.05).	Bae et al. (2004)
2	RBEP (50mg/kg BW p.o. & i.p., 250 mg/kg BW p.o. for 14 days)	(1) ICR mice + S-180; (2) C57/Bl6 mice + B16/Bl6 melanoma	(1) RBEP prolonged survival by 14.6% (31.4 days), 30.3% (35.7 days), and 38.0% (37.8 days) with 50 mg/kg, 250 mg/kg p.o., and 50 mg/kg i.p., respectively. (2) TW ↓35.6% with 50 mg/kg p.o., ↓41.7% (2.155g) 250 mg/kg p.o., and ↓55.1% (1.66g) with 50 mg/kg i.p.	Kim et al. (2007)
3	Biobran MGN-3 (40 mg/kg BW i.p. over 3 weeks & i.t. over 5 weeks)	Swiss albino mice + SEC	TV (i.p.) was significantly lower than control starting from day 14 (p < 0.05) and ↓63.27% (p < 0.01) at day 35; TW (i.p.) was also significantly lower (3.63 ± 0.45 vs. 6.62 ± 0.38, p < 0.01) compared to the control at day 35. Significant TV (i.t.) reduction from observed from day 28, reaching a ↓44.83% (p < 0.01) difference with control on day 45.	Badr El-Din et al. (2008)
4	Biobran MGN-3 (25 mg/kg BW i.p. over 25 days)	Swiss albino mice + SEC	Early treatment (from day 4) TV ↓54% & TW ↓34% (p < 0.01) relative to the control. Late treatment (from day 11) TV ↓24% & TW ↓12% (p < 0.05).	Noaman et al. (2008)
5	RBEP (250 mg/kg p.o. or i.p. for > 2 weeks	ICR mice + S-180 cells	Survival rate: p.o. 5.3% higher (19.9 vs. 18.9 days), and i.p. 23.2% higher (23 vs. 18.7 days), compared to controls. RBEP-treated mice have significantly lower BW than controls starting from day 13 (p.o.) and day 10 (i.p.).	An (2011)
6	C3G-F (250 mg/kg p.o. for 2 or 3 weeks	(1) ICR mice + S-180; (2) C57/Bl6 mice + B16/Bl6 melanoma	(1) BW: significant difference (p < 0.05) since day 8. C3G-F prevented BW gain (6.5 g vs. 11.8 g, ↓60%) on day 15. (2) TW: ↓19.4% in C3G-F group vs. control (0.514 ± 0.129 g vs. 0.635 ± 0.241 g, p < 0.05) at 3 weeks.	Kim et al. (2011)
7	NK cells activated with 100mg/mL Biobran MGN-3 i.v. 2 ×/week for 4 weeks	NOD-scid IL-2Rgnull mice + NB-1691luc	RBAC-activated NK cell treatment significantly lowered TV (p < 0.05) under bioluminescence imaging and extended the survival time of the mice than fresh NK cell therapy or no treatment.	Pérez-Martínez et al. (2015)
8	Biobran MGN-3 (40mg/kg BW i.p. 3 ×/week for 3 weeks)	Swiss albino mice + SEC	RBAC significantly reduced BW loss in SEC-bearing mice (↓4.1% vs. 18%, p < 0.01) and TW (↓46.3%, p < 0.01) compared to control by day 30. Continuous suppression of TV was detected (day 14: ↓33.7%, day 30: ↓49.9%, p < 0.01).	Badr El-Din et al. (2019)

Abbreviations: BW: body weight; C3G-F: fermented SuperC3GHi bran; i.p.: intraperitoneal injection; i.t.: intratumoral injection; i.v. intravenous; NK: natural killer; p.o.: per oral; RBAC: rice bran arabinoxylan compound; RBEP: rice bran exo-biopolymer; SEC: solid Ehrlich carcinoma; TV: tumour volume in mm³; TW: tumour weight in gram.

Table 3. The direct anticancer effects of RBAC and the potential mechanisms.

#	RBAC (dose)	Model	Key Findings	Reference
A. Promotion of cancer cell apoptosis
1	Biobran MGN-3 (concentration not reported)	In vitro. SCC13 cell line.	A 30% decrease in cell numbers after 48 hours and 50% at 72 hours after incubation with RBAC was detected. Untreated SCC13 cells continued to grow over time. Also found was increased secretion of IL-10 and IL-12 of SCC13 cells by RBAC.	Ghoneum et al. (2000)
2	Biobran MGN-3 (100, 500 & 1000 mg/mL)	In vitro. MCF-7 cell line.	Cell survival rates were dose-dependent: 75%, 70%, and 63% after 3 days of incubation with 100, 500, and 1000 mg/mL of RBAC, respectively.	Gollapudi and Ghoneum (2008)
3	Biobran MGN-3 (100–1000 μg/mL)	In vitro. MCF-7 & 4T1 cell lines.	IC50 (MCF-7) was 800 μg/mL at 24 hours and about 1000 μg/mL at 48 hours. IC50 (4T1) being 700 μg/mL at 24 hours and 580 μg/mL at 48 hours.	Ghoneum et al. (2014)
4	Biobran MGN-3 (0–1000 μg/mL)	In vitro. PC3 & LNCaP cell lines.	Significantly decreases (p < 0.05) in the cancer cell proliferation in a dose- and time-dependent manner (24, 48, and 72 h).	Brush et al. (2010)
5	Biobran MGN-3 (100–1000 μg/mL)	In vitro. HUT 78 cell line. Anti-CD95 antibodies.	Treatment of HUT 78 cells with RBAC (for 3 hours) before incubating with anti-CD95 antibodies increased the specific apoptosis significantly (p < 0.01) by 35–42 %, about double that of Anti-CD95 antibodies alone. The escalation in apoptosis was not associated with the upregulation of death receptor expression but through sensitizing the receptor.	Ghoneum and Gollapudi (2003)
6	Biobran MGN-3 (40 mg/kg BW p.o. every other day for 8 months)	Wistar rats + carcinogen (MNNG)	RBAC mitigated the carcinogenesis effects of MNNG by causing a significant increase in cell-cycle arrest in the SubG1 phase (p < 0.01) compared to the control, with the AI/PrI ratio increased by 1.67-fold. RBAC increased the apoptotic cancer cells in tumour tissues by 63.7% (p < 0.01), most prominently in early apoptosis (230.1%, p < 0.01). Downregulation of Bcl-2 and upregulation of P53, Bax, Bax/Bcl-2 ratio, and caspase-3 were detected.	Badr El-Din et al. (2016a)
7	Biobran MGN-3 (40 mg/kg BW i.p. 3×/week for 3 weeks)	In vivo. Swiss albino mice + SEC	RBAC markedly increased cell-cycle arrest in the sub-G1 phase was detected by 102% (p < 0.01) in the RBAC group compared to the control. RBAC treatment also increased the AI/PrI ratio by 2-fold (p < 0.01). The quantitative histochemical analysis also showed reduced viable cells (28.2 ± 1.25% vs. 74.5 ± 2.25%) and increased apoptotic cells (53.1 ± 1.21% vs. 18.2 ± 1.68%) in the tumor tissues of RBAC-treated mice than control. RBAC significantly (p < 0.01) upregulated p53, Bax, and caspase-3 while downregulated Bcl-2 gene expression.	Badr El-Din et al. (2019)
8	Biobran MGN-3 (25 mg/kg BW i.p. 5 ×/week, either for 12 or 22 weeks)	Wistar albino rats + carcinogen (NDEA + CCl4)	Cell-cycle arrest in the sub-G1 phase was markedly increased by 126 and 99% (p < 0.01) through pretreatment and posttreatment of RBAC. RBAC treatment (pre, post) significantly reduced (p < 0.01) viable cells (↓74.51%, ↓72.54%) and necrosis (↑89%, ↑75.47%) while increased early (↑316%, ↑309%) and late (↑255%, ↑237%) apoptosis, compared to carcinogen-untreated rats. RBAC significantly (p < 0.01) upregulated p53, Bax, and caspase-3 while downregulated Bcl-2 gene expression.	Badr El-Din et al. (2020)
B. Prevention of oxidative stress
9	Biobran MGN-3 (25 mg/kg BW i.p. 6 x/week for 25 days)	In vivo. Swiss albino mice + SEC	Mice treated with RBAC did not show elevated MDA like untreated mice and had significantly higher GSH levels (p < 0.01) in the blood, liver, and tumour. GPx, GST, SOD, and CAT and the related gene expressions in RBAC-treated mice were also significantly higher (p < 0.01) than in untreated mice.	Noaman et al. (2008)
C. Modulating cytokine production
10	RBAC (40 mg/kg BW i.p. over 3 weeks & i.t. over 5 weeks)	In vivo. Swiss albino mice + SEC	RBAC treatment showed a significantly increased TNF-α (↑15.63%) and IFN-γ (↑154.54%) compared to control. Untreated SEC mice showed elevated IL-10 (↑111.71%), but the increase was dampened in RBAC-treated mice (↑14.75%, p < 0.01).	Badr El-Din et al. (2008)
11	Biobran MGN-3 (2 g/day p.o. for 3 months)	RCT. MM patients (n = 48, RBAC = 32, placebo = 12)	RBAC significantly elevated (p < 0.05) both Th1 cytokines (IFN-γ, IL-12, IL-17, TNF-α) and Th2 cytokines (IL-4, IL-6, IL-9, IL-10, and IL-13) over placebo after 3 months.	Cholujova et al. (2013)
12	ONS with 0.4 g of RBEP p.o. for 8 weeks	NRCT. Various malignancies (n = 34, RBAC = 10, control = 24)	RBAC significantly lowered (p < 0.05) IL-1β, IL-6 and IL-8 and increased IL-12p70 (p < 0.05) compared to the control group. A marginally significant rise (p = 0.056) in the IL-10 level in the RBAC group compared to baseline was also detected.	Kim et al. (2020)

Abbreviations: AI/PrI: the ratio of the apoptotic index over the proliferation index; BW: body weight; CAT: catalase; CCI₄: carbon tetrachloride; CD: cluster of differentiation; GPx: glutathione peroxidase; GST: glutathione S-transferases; GSH: glutathione; IC₅₀: half maximal inhibitory concentration; IFN: interferon; IL: interleukin; i.p.: intraperitoneal; i.t.: intratumoral; MDA: malondialdehyde; MM: multiple myeloma; MNNG: methylnitronitrosoguanidine; NDEA: N-nitrosodiethyamine; NRCT: nonrandomized controlled trial; ONS: oral nutritional supplement; p.o.: per oral; RBAC: rice bran arabinoxylan compound; RBEP: rice bran exo-biopolymer; RCT: randomized controlled trial; SEC: solid Ehrlich carcinoma; SOD: superoxide dismutase; TNF: tumour necrosis factor.

Figure 3. The anticancer effect of RBAC is achieved through both the intrinsic pathway via the increased susceptibility of CD95 (Fas/APO-1) ligands in the cancerous cells to promote apoptosis and the extrinsic pathway through the downregulation of the antiapoptotic Bcl-2 proteins to lower membrane potentials, leading to the upregulation of the tumour-suppressing P53 gene and the upregulated production of the apoptotic Bax and caspase-3 signalling proteins. Malignant cell proliferation is arrested with evidence of increased hypodiploid cell counts in the SubG1 phase in cell cycle analysis. The antioxidant and cytokine-modulating capacities of RBAC also augment proapoptotic activity.

Table 4. In vivo studies investigating the chemoprevention activities of RBAC.

#	RBAC (dose)	Model	Key Findings	Reference
1	Biobran MGN-3 (40 mg/kg BW p.o. every other day for 8 months)	Wistar rats + carcinogen (MNNG)	Untreated rats developed mild- and high-grade gastric glandular dysplasia (6/10, 60%) and invasive carcinoma (2/10, 20%). RBAC-treated rats had significantly lower incidence (p < 0.01) of mild dysplasia, of which were patchy and small (3.5/12, 29.2%) and carcinoma in situ only (1/12, 8.3%). RBAC also significantly lower Ki-67 tumour proliferation marker expression (39.8% vs. 50.8%, p < 0.001).	Badr El-Din, et al. (2016a)
2	Biobran MGN-3 (25 mg/kg BW i.p. 5 x/week, either for 12 or 22 weeks)	Wistar rats + carcinogen (NDEA + CCl4)	Both RBAC treatment regimes kept the liver weight at the normal range and significantly reduced (p < 0.01) weight loss caused by the carcinogens. Among RBAC-pretreated rats, the liver tissues showed minimal changes in hepatocyte morphology and histology with no inflammation. In contrast, moderate liver damage was observed in the posttreatment group but with only a few degenerated hepatocytes.	Badr El-Din et al (2016c)

Abbreviations: BW: body weight; CCI₄: carbon tetrachloride; i.p.: intraperitoneal; MNNG: methylnitronitrosoguanidine; NDEA: N-nitrosodiethyamine; p.o.: per oral; RBAC: rice bran arabinoxylan compound.

Table 5. Results from in vitro, in vivo, and human studies on the synergistic effects of RBAC with chemotherapeutic agents.

#	RBAC (dose)	Study Design	Key Findings	Reference
1	Biobran MGN-3 (100, 500 & 1000 µg/mL)	In vitro. MCF-7 and HCC70 + daunorubicin	RBAC + daunorubicin lowered the IC50 values against MCF-7 cells by 3-, 5- and 5.5-fold at 100, 500, and 1000 µg/mL, respectively. The IC50 of daunorubicin for HCC70 cells was also consistently decreased by 2.5-fold with RBAC. RBAC enhanced drug transport with increased accumulation of daunorubicin in cells.	Gollapudi and Ghoneum (2008)
2	Biobran MGN-3 (1 g/day p.o. for 1 year)	RCT. Liver cancer (n = 68, RBAC = 38, control = 30) + TOCE + PEIT	RBAC significantly improved (p < 0.01) the treatment response rate (89% vs. 80%), lowered the AFP marker (↓38% vs. ↑7%), and decreased TV (↓36% vs. ↑0.2%). During the 3 years follow-up, the RBAC group showed lower recurrence and higher survival rates.	Bang et al. (2010)
3	Biobran MGN-3 (600, 750 & 1000 µg/mL)	In vitro. MCF-7 and 4T1 + paclitaxel	RBAC + paclitaxel lowered the IC50 values against MCF-7 cells by a factor of 100. For 4T1 cells, the IC50 value for paclitaxel at 24 hours decreased by a factor of ∼3 at 600 μg/mL of RBAC and up to a factor of ∼100 at 1000 μg/mL.	Ghoneum et al. (2014)
4	Biobran MGN-3 (40 mg/kg BW for 30 days)	Swiss albino mice + SEC + paclitaxel (2 mg/kg BW)	The combination therapy significantly reduced (p < 0.01) TV by 88.3% compared to no treatment. The TV reduction was more pronounced than the effects of either paclitaxel (↓58.9%) or RBAC (↓77.1%) alone. RBAC + paclitaxel also increased inhibition of tumour proliferation, cancer cell apoptosis, and downregulation of Ki-67 expression.	Badr El-din, et al. (2016b)

Abbreviations: AFP: alpha-fetoprotein; IC₅₀: half maximal inhibitory concentration; PEIT: percutaneous ethanol injection treatment; p.o.: per oral; RBAC: rice bran arabinoxylan compound; RCT: randomized controlled trial; TOCE: transarterial oily chemoembolization; TV: tumour volume.

Table 6. Results from animal and human studies on the protective effects of RBAC against the toxicity of chemotherapeutic agents.

#	RBAC (dose)	Study Design	Key Findings	Reference
1	Biobran MGN-3 (0, 5, or 50 mg/kg BW p.o. daily for 11 days)	Sprague-Dawley albino rats + cisplatin (9 mg/kg BW) or doxorubicin (10 mg/kg BW)	RBAC prevented weight loss induced by the chemotherapeutic agents (p < 0.05). RBAC at 5 mg/kg BW appeared more effective than at the higher dose of 50 mg/kg in preventing the toxicity and side effects of cisplatin and doxorubicin.	Jacoby et al. (2001)
2	Biobran MGN-3 (1 mg/day p.o. and i.p. for 28 days)	BALB/c mice + cisplatin (15 mg/kg BW i.p.)	Statistically significant differences (p < 0.05) in BW were detected in phases II (weight loss), III (weight gain), and IV (weight stabilizing) of both groups of RBAC (i.p. and p.o.) compared to their respective control groups with the RBAC groups showing trends of reduced weight loss and faster weight recovery over time.	Endo and Kanbayashi (2003)
3	Biobran MGN-3 (3 g/day p.o. 1 week before and 1 week after chemo cycle for 6 cycles)	RCT. Breast cancer patients (n = 50) receiving chemotherapy	The study found significant differences (p < 0.001) in the proportions of patients experiencing anorexia/tiredness (RBAC vs. control: 20% vs. 88%), nausea/vomiting (40% vs. 100%), hair loss (28% vs. 100%) between the two groups. 84% of the control group experienced weight loss but none in the RBAC group.	Masood et al. (2013)

Abbreviations: BW: body weight; i.p.: intraperitoneal injection; p.o.: per oral; RBAC: rice bran arabinoxylan compound; RCT: randomized controlled trial.

Table 7. Results from animal and human studies on RBAC’s synergy with and protection against the adverse effects of radiation treatment.

#	RBAC (dose)	Study Design	Key Findings	Reference
1	Biobran MGN-3 (40 mg/kg BW i.p. q.o.d. for 6 weeks)	Swiss albino mice (n = 6) with single dose whole-body γ-Rad	Significantly lesser (p < 0.05) BW loss at weeks 1 and 4 after Rad than the control group. RBAC reduced (p < 0.05) the kidney and liver organ weight loss induced by Rad at week 1 and prevented anemia, lymphopenia, neutrophilia, and thrombocytopenia caused by Rad damage.	Ghoneum et al. (2013)
2	Biobran MGN-3 (40 mg/kg BW i.p. 5×/week for 3 weeks)	Swiss albino mice + SEC with whole-body X-ray Rad (3 doses)	RBAC + Rad significantly prevented Rad-induced BW loss (p < 0.01). RBAC + Rad achieved the highest reduction in TV and TW compared to Rad alone (p < 0.01) and RBAC alone (p < 0.05). RBAC + Rad increased apoptosis in tumour tissues with the highest cell-cycle arrest while maximizing the AI/PrI ratio at 2.2-fold (p < 0.01) compared to untreated SEC-bearing mice. Increased apoptotic regulators and their corresponding gene expression were also detected.	Badr El-Din et al. (2019)
3	Biobran MGN-3 (40 mg/kg BW i.p. q.o.d. for 6 weeks)	C57BL/6 mice (n = 6) with single dose abdominal precision irradiation	After irradiation, RBAC prevented the depletion of mitochondrial respiratory chain complexes and intercellular ATP content in mice’s jejunal and colonic tissues by strengthening the endogenous antioxidative activities and total antioxidant capacity.	Zhao et al. (2020)
4	Biobran MGN-3 (3 g/day 2 weeks before and 2 months after)	RCT. Head & neck cancer patients undergoing chemoradiotherapy (n = 65, RBAC = 32, placebo = 33)	Significant between-group differences (p < 0.05) were in Hb, haematocrit, RBC, platelets, neutrophils, and lymphocytes after 2 months, favouring RBAC. The RBAC group reported significantly (p = 0.05) better QoL and lower mortality, blood transfusion, hospitalisation, and metastasis.	Tan and Flores (2020)

Abbreviations: ATP: adenosine triphosphate; BW: body weight; Hb: haemoglobin; i.p.: intraperitoneal injection; q.o.d.: every other day; QoL: quality of life; Rad: radiation therapy; RBAC: rice bran arabinoxylan compound; RBC: red blood cells; RCT: randomized controlled trial; TV: tumour volume; TW: tumour weight.

Table 8. Results from animal and human studies on the synergistic effects of RBAC with other natural products.

#	RBAC (dose)	Study Design	Key Findings	Reference
1	Biobran MGN-3 (100, 500 & 1000 mg/mL)	In vitro. MCF-7 cell line + yeast (1:10 ratio)	RBAC significantly increased yeast attachment (54% vs. 27%, p < 0.001) and phagocytosis rate (72% vs. 23%, p < 0.01) than control at 0.5 h. RBAC caused dose-dependent increases in phagocytosis-induced cell death of 35.4, 40.1, and 33.04% at 100, 500, and 1000 µg/mL, respectively.	Ghoneum and Gollapudi (2005a)
2	Biobran MGN-3 (100 mg/mL)	In vitro. Monolayer MCF-7 cells + yeast (1:10 ratio)	RBAC increased the magnitude of phagocytizing of yeast by MCF-7 cells by 2- to 3-fold after 1 to 4 h. Culturing with RBAC, yeast, or yeast + RBAC caused 58, 85, and 92% cell death, respectively, compared to only 9.5% in untreated MCF-7 cells.	Ghoneum and Gollapudi (2005b)
3	Biobran MGN-3 (50 and 100 μg/mL)	In vitro. MM U266 cell line + curcumin (2.5–10 μM)	RBAC + curcumin caused a significant decrease (p < 0.0005) in cell survival compared to either agent alone and achieved an 87% decrease in cell count at 100 μg/mL RBAC and 10 μM curcumin. Combining RBAC (50 μg/ml) with curcumin significantly increased apoptosis (p < 0.05) to 20.0, 22.0, and 24.7% at 2.5, 5, 10 μM, respectively, compared to control.	Ghoneum and Gollapudi (2011)
4	Biobran MGN-3 (12 to 45 mg/kg BW 2×/week) for ≥6 months	Cross-section survey. Patients with advanced cancer (n = 35) + mistletoe extract (5 mg 2 x/week)	Improvement in physical activity (71%) and appetite (66%) were two of the most important effects reported by the patients. For those concurrently treated with conventional treatment (n = 24), 70.8% (17/24) also cited reducing side effects as a benefit.	Hajtó et al. (2016b)
5	Biobran MGN-3 (1 g/day for 24 weeks)	RCT. Cancer patients with CFS (n = 48, RBAC = 24, control = 24) + oncothermia	RBAC + oncothermia significantly lowered the posttreatment mean CFQ score (14.6 ± 2.3 vs. 23.9 ± 2.3, p < 0.01) from baseline. The control group with no treatment reported no significant change in mean CFQ. The mean PGIC score of the RBAC group was 2.1 ± 0.5 (much improved after treatment) compared to 4.3 ± 0.9 (no change) of the control group.	Petrovics et al. (2016)

Abbreviations: BW: body weight; CFQ: Chalder fatigue scale; CFS: chronic fatigue syndrome; MM: multiple myeloma; PGIC: patient global impression of change scale; qol: quality of life; rbac: rice bran arabinoxylan compound.

Figure 4. A summary of the potential benefits of RBAC in cancer treatment.

Table 9. A summary of all RBAC randomized controlled trials with survival and/or quality of life as outcome measures.

		N (male/female) age (year)		Interventions
Authors (Year)	Condition	RBAC	Control	RBAC	Control	Concomitants	Time points	Outcome measures	Results
Takahara and Sano (2004)	Progressive cancer (multiple types) stage III –IV	96 (55/41) µ = 56.0	109 (59/50) µ = 53.5	Biobran MGN-3 (3 g/day p.o., 18 months)	NC	CAT + anticancer drugs with fewer side effects	18 months	Survival. QoL: pain, malaise, nausea, appetite.	SR: T (54.2%, 52/96) > C (33.9%, 19/56, PP), p < 0.05 > C (17.4%, 19/109, ITT), p < 0.001. QoL (T vs C): pain (-15.9 ≈ −14.0%), malaise (-17.3 ≈ −17.1%), nausea (-13.3 ≈ −14.6%), appetite (+24.2 > +15.2%).
Bang et al. (2010)	Liver cancer	38 (30/8) µ = 49 ± 19	30 (24/6) µ = 51 ± 17	Biobran MGN-3 (1 g/day, 1 year)	NC	TOCE + PEIT	12, 24, 36 months	Survival.	SR (12, 24, 36 months): T (76, 35, 11%) > C (63, 6.7, 0%), p < 0.01 (12 & 24 months)
Masood et al. (2013)	Locally advanced breast cancer	25 (0/25)	25 (0/25)	Biobran MGN-3 (3g/day, before & after each cycle)	NC	CT x 6 cycles	∼18 weeks	QoL: anorexia, nausea, alopecia, weight.	QoL (T vs C): anorexia (20 < 88%), nausea (40 < 100%), alopecia (28 < 100%), weight gain (64 > 0%), weight loss (0 < 84%), p < 0.001.
Itoh et al. (2015)	Cervical cancer	7 (0/7) µ = 49.9	7 (0/7) µ = 57	Biobran MGN-3 (3g/day, 4 weeks)	Placebo	CT + RT (50.4 Gy in 28 fractions)	4 weeks	QoL: nausea, diarrhea, diarrhea agent.	QoL: T < C in nausea and diarrhea, diarrhea agent but p > 0.05.
Petrovics et al. (2016)	Cancer (multiple types) with CFS	24	24	Biobran MGN-3 (1 g/day, 24 weeks) + Oncothermia	NC	CT and/or RT	24 weeks	QoL: pain, QLQ-C3 (physical, emotional, general), fatigue (CFQ, PGIC).	QoL: T < C in pain, physical, emotional & general QoL, but no data reported. Fatigue (T vs C): CFQ (14.6 ± 2.3 < 23.2 ± 7.2), PGIC (2.1 ± 0.5 < 4.3 ± 0.9), p < 0.001.
		(20/28) M = 66
Tan and Flores (2020)	H&N cancer (stage II –IV)	32 (24/8)M = 49	33 (29/4 M = 54.5	Biobran MGN-3 (3 g/day 2 weeks before and 2 months after RT)	Placebo	RT or CT + RT (60-70 Gy in 30 – 35 fractions)	∼18 weeks	Survival. QoL: weight, QLQ-C3 H&N35 (general), radiation toxicity.	SR: T (0%, 0/32) > C (33.3%, 11/33), p < 0.001. QoL: p > 0.05 for weight loss and radiation toxicity. General QoL, T (1.53 ± 0.24) < C (1.72 ± 0.33), p < 0.019.

Abbreviations: C: comparator; CAT: complementary and alternative therapies; CFQ: Chalder fatigue scale; CFS: chronic fatigue syndrome; H&N: head and neck; NC: no comparator; CT: chemotherapy; ITT: intention to treat; M: median; µ: mean; PEIT: percutaneous ethanol injection treatment; PGIC: patient global impression of change scale; PP: per protocol; QLQ-C3: European Organisation for Research and Treatment of Cancer’s Quality of Life Questionnaire version 3.0; QoL: quality of life; RT: radiation therapy; SR: survival rate; T: treatment; TOCE: transarterial oily chemoembolization.

Figure 5. Forest Plot of survival events of RBAC-treated group compared to those of the control group.

Figure 6. A Bubble chart visualizing the available evidence on the effect of RBAC on cancer patients’ quality of life (QoL). Each bubble represents an outcome assessed in one study, with the sample size defining the diameter of the bubble. Each study is assigned a different colour. X-axis: Statistical significance (p-value) of the outcome; Y-axis: QoL outcome measures.

Figure 7. A summary of the quality assessment results by study.

Figure 8. A Chart summarizing the quality assessment outcomes by types of bias.

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Data availability statement

All data used in this study will be available via email to the corresponding author upon request.