The initial search yielded a total of 1278 studies. After excluding 274 irrelevant and duplicate studies, the full texts of 1004 studies were screened. Of these, 148 were considered eligible based on the availability of full texts as well as the description of target outcomes. Ultimately, 113 articles were removed (no full texts, n=43; no target outcomes, n=70), and 35 studies were selected. A detailed description of the steps followed during the retrieval process is provided in Figure 1.
Of 35 selected studies, 21 were in vitro studies (Table 1), 11 were in vivo studies with animal models (Table 2), and three were clinical trials (Table 3). In in vitro studies, the most studied cancer was breast cancer (five studies) (Yang et al. 2019; Wu et al. 2019; Yang et al. 2016; Kim et al. 2016; Duan et al. 2014), while the A549 non-small cell lung cancer (NSCLC) cell line was the one most commonly used cell line (four studies) (Wu et al. 2018; Chen et al. 2018; Butcher et al. 2018; Wang et al. 2017). Three studies (Sharma et al. 2016; Rezkk et al. 2013; Dastjerdi et al. 2014) examined DSF as a single agent, and 17 studies (Yang et al. 2019; Wu et al. 2019; Yang et al. 2016; Kim et al. 2016; Duan et al. 2014; Wu et al. 2018; Chen et al. 2018; Butcher et al. 2018; Wang et al. 2017; Guo et al. 2019; Albers et al. 2018; Yang et al. 2017; AbuSerie et al. 2017; Zhao et al. 2015; Zhang et al. 2015; Han et al. 2013; Cen et al. 2002) examined DSF in combination with metal ions (Cu, Ag), chemotherapy, or radiation therapy. In addition, in three studies, DSF was encapsulated in nanoparticles (DSF-NPs) (Duan et al. 2014; Wang et al. 2017; Zhang et al. 2015).
Table 1
Effects of disulfiram on cell apoptosis rates from in vitro studies
Reference
|
Country
|
Tumor
|
|
|
|
|
Percentage of apoptosis (%)
|
Intervention
time
|
Negative control
|
Posivitive control
|
Cell lines
|
Negative control
|
Positive control
|
Treatment group
|
You et al (42)
|
China
|
Colorectal cancer
|
48hous
|
Saline
|
DOX
(8.5 μM)
|
HCT116
|
0.27 ± 0.24
|
29.2 ± 4.1
|
DSF/Cu 0.05 μM: 8.55 ± 2.3, 0.1 μM: 24.02 ± 3.6, 0.2 μM: 38.4 ± 7.9, 0.4 μM: 58.3 ± 7.7
|
HCT8
|
2.1±1.6
|
32.3 ± 4.1
|
DSF/Cu 0.05 μM: 29.5 ± 4.4, 0.1 μM: 28.1 ± 9.5, 0.2 μM: 38.6 ± 10.3, 0.4 μM: 56.4 ± 10.2
|
SW620
|
2.21±0.5
|
48.4 ± 9.5
|
DSF/Cu 0.05 μM: 20.1±5.7, 0.1 μM: 30 ± 4.2, 0.2 μM: 42 ± 6.3, 0.4 μM: 43.45 ± 8.3
|
Yang et al (8)
|
Germany
|
Breast cancer
|
48hours
|
Control
|
CIS
(5 μM)
|
MCF-7
|
25.31
|
31.67
|
DSF 1 μM: 36.6, DSF 1 μM + CIS 5 μM: 57.4
|
MDA-MB-435S
|
5.843
|
5.447
|
DSF 1 μM: 13.56, DSF 1 μM + CIS 5 μM: 29.4
|
SKB-R3
|
3.023
|
11.46
|
DSF 1 μM: 5.6, DSF 1 μM + CIS 5 μM: 7.71
|
Wu et al (9)
|
China
|
Triple-negative breast cancer
|
24hours
|
DMSO
|
PAX
(5 nM)
|
SUM102 ALDH+
|
2.22
|
5.83
|
DSF/Cu 0.75 μM: 23.53
|
SUM102 ALDH-
|
8.01
|
10.81
|
DSF/Cu 0.75 μM: 20.9
|
Guo et al (20)
|
Germany
|
Ovarian cancer
|
72hours
|
Control
|
_
|
IGROV1
|
10.32
|
_
|
Cu 1 μM: 15.3, DSF 1 μM: 25.46, DSF/Cu: 47.55
|
SKOV3IP1
|
8.69
|
Cu 1 μM: 7.1, DSF 0.1 μM: 15.99, DSF/Cu: 55
|
SKOV3
|
3.65
|
Cu 1 μM: 1.91, DSF 1 μM: 43.2, DSF/Cu: 50.4
|
Wu et al (13)
|
China
|
Non-small cell lung cancer
|
24hours
|
Control
|
_
|
A549
|
2.5
|
_
|
Cu 1 μM: 3.8, DSF 1.4 μM: 4.8, DSF/Cu: 35.4
|
H460
|
4.7
|
Cu 1 μM: 3.7, DSF 8 μM: 4.9, DSF/Cu: 21.4
|
H1299
|
8.7
|
Cu 1 μM: 10.3, DSF 4 μM: 7.1, DSF/Cu: 37.9
|
Chen et al (14)
|
China
|
Non-small cell lung cancer
|
24hours
|
Control
|
_
|
A549
|
3.35
|
_
|
Ag 1.25 μM: 4.34, DSF 1.25 μM: 5.14, DSF/Ag: 42.81
|
Butcher et al (15)
|
UK
|
Non-small cell lung cancer
|
16hours
|
Vehicle
|
_
|
A549
|
6.3
|
_
|
CuCl2 10 μM: 6.5, DSF 1 μM: 15.2, DSF/CuCL2: 47.2
|
Albers et al (21)
|
Germany
|
Head and neck squamous
|
48hours
|
Control
|
CIS(1μM)+10Gy
|
HNSCC cell lines
|
11.35
|
CIS 1 μM: 24.12, 10Gy: 23.47
|
DSF 3 μM/Cu 0.1 μM: 20.87, DSF 3 μM + CIS 1 μM: 38.35, DSF 3 μM/Cu 0.1 μM + CIS 1 μM: 51
|
cell carcinoma
|
CIS 1 μM + 10Gy: 30.68
|
DSF 3 μM: 17.66, CIS 1 μM + 10Gy+ DSF 3 μM: 44.82, CIS 1 μM + 10Gy+ DSF 3 μM/Cu 0.1 μM: 61.5
|
Yang et al (22)
|
China
|
Nasopharyngeal cancer
|
6hours
|
Control
|
_
|
CNE-2Z
|
4.41
|
_
|
DSF 0.2 μM/Cu 10 μM: 24.08, DSF 0.4 μM/Cu 10 μM: 58.2
|
NP69-SV40T
|
0.55
|
_
|
DSF 0.2 μM/Cu 10 μM: 1.19, DSF 0.4 μM/Cu 10 μM: 5.99
|
Marwa et al (23)
|
Egypt
|
Colon Cancer
|
72hours
|
Control
|
_
|
DCECs
|
1.58
|
_
|
DSF 9.5 ± 0.9 μg/mL: 60.31 ± 1.2, UC-NPs 1548.7 ± 25 μg/mL: 12.12 ± 0.47, C-NPs 3122.4 ± 39 μg/mL: 2.6 ± 0.07
|
CDCECs
|
0.28
|
_
|
DSF 23.9 ± 0.1 μg/mL: 57.78 ± 0.34, UC-NPs 77.7 ± 1.4 μg/mL: 54.75 ± 1.24, C-NPs 93.8 ± 0.4 μg/mL: 47.5 ± 0.31
|
Caco-2
|
0.05
|
_
|
DSF 39.6 ± 0.3 μg/mL: 53.62 ± 0.53, UC-NPs 97.9 ± 0.5 μg/mL: 53.49 ± 0.59, C-NPs 148.3 ± 0.1 μg/mL: 40.28 ± 0.24
|
Wang et al (16)
|
China
|
Non-small cell lung cancer
|
24hours
|
Control
|
_
|
A549
|
0.45
|
_
|
DSF-LP-PLGA-MP 1, 3, 5, 7days: 9.32, 27.1, 28.2, 49.18
|
Yang et al (10)
|
China
|
Breast cancer
|
24hours
|
Control
|
_
|
MCF-7
|
0.29
|
_
|
DSF 0.2 μM/CuCl2 10 μM: 27.56, DSF 0.25μM/CuCl2 10 μM: 86.8
|
Kim et al (11)
|
Korea
|
HER2-positive breast cancer
|
24hours
|
DMSO
|
_
|
SKBR3
|
3.16
|
_
|
Cu 1 μM: 2.91, DSF 1 μM: 2.6, DSF/Cu: 30.21
|
BT474
|
2.49
|
_
|
Cu 1 μM: 2.88, DSF 1 μM: 8, DSF/Cu: 40.76
|
Sharma et al (17)
|
India
|
Prostatic cancer
|
48hours
|
Control
|
STA (3mM)
|
PC3
|
8.34±2.2
|
26.31±5.5
|
DSF 1 μM: 15.04±3.14, DSF 2 μM: 19.71±4.2, DSF 3 μM: 32.06±6.16
|
DU145
|
13.67±2.66
|
41.31±4.47
|
DSF 1 μM: 10.89±1.56, DSF 2 μM: 42.81±4.56, DSF 3 μM: 47.23±4.85
|
Zhao et al (24)
|
China
|
Pituitary adenomas
|
24hours
|
Control
|
TMZ
(100μM)
|
Pituitary adenoma cells
|
0.29±0.09
|
0.81±0.23
|
DSF 25 μM: 0.31±0.10, DSF 25 μM + TMZ 100 μM: 1.64±0.16
|
Zhang et al (25)
|
China
|
Hepatocellular carcinoma
|
24hours
|
Control
|
_
|
Hep G2 cells
|
1.3
|
_
|
DSF-S-LNCs (PH=7.4) : 9.4, DSF-S-LNCs (PH=6.5) : 16.5
|
Duan et al (12)
|
China
|
Breast cancer
|
24hours
|
Control
|
_
|
4T1
|
1.07
|
_
|
DSF 1 μg: 34.77, DnMs (DSF 1 μg): 34.37, DCM (DSF 1 μg): 41.11
|
Rezk et al (18)
|
USA
|
Ovarian cancer
|
72hours
|
Control
|
_
|
A2780DK
|
4.15
|
_
|
DSF 5 μM: 36.4
|
Dastjerdi et al (19)
|
Iran
|
Pancreatic cancer
|
24hours
|
Control
|
_
|
PANC-1
|
27
|
_
|
DSF 5 μM: 51, DSF 10 μM: 84, DSF 13 μM: 92
|
Han et al (26)
|
China
|
Pancreatic cancer
|
72hours
|
Control
|
_
|
SW1990
|
1.5
|
_
|
DDTC–Cu(I) 1 μM: 6.4, DDTC–Cu(I) 3 μM: 17.7, DDTC–Cu(I) 5 μM: 24.8
|
Cen et al (27)
|
USA
|
Melanoma
|
48hours
|
Control
|
BSO (100M)
|
C81-46A
|
12.057±0.72
|
13.194±1.11
|
DSF 50 ng/ml: 25.35 ± 1.21, DSF 50 ng/ml + BSO 100 M: 54.78 ± 2.83
|
Abbreviations: DOX, doxorubicin; CIS, cisplatin; PTX, paclitacel; STA, staurosporine; TMZ, temozolomide; BSO, buthionine-sulfoximine; DnMs: DSF loaded noncrosslinked micelles; DCM, DSF loaded redoxsensitive shell crosslinked micelle; DSF-LP-PLGA-MP, Disulfiram-loaded porous PLGA microparticle; UC-NPs, uncoated NPs; C-NPs, coated NPs; DDTC–Cu(I), diethyldithiocarbamate-Cu(I).
|
Table 2
Effects of disulfiram on tumor inhibition rate from animal studies
Information of reference
|
Information of animals
|
Intervention and tumor inhibition rate
|
Toxicity evaluation
|
|
Reference
|
Country
|
Tumor
|
Strain and gender
|
Old (weeks)
|
Weight (g)
|
Animal tumor model
|
Interveniton
methods
|
Negative control
|
Positive control
|
Treatment group
|
Inhibit Rate
|
Parameter
|
Outcome
|
|
|
Peng et al(28)
|
China
|
Lung cancer
|
Female
Balb/C nude mice
|
4−5
|
18−22
|
1.0 × 106 A549 cells, SC, right flank
|
every 4 days with 4 times, iv
|
Saline
|
_
|
DSF 10 mg/kg + copper 1.5 mg/kg ig PNpL-DSF/Cu(II)/DDC (1:1, 1mg/kg)
|
TSR% =16.6% TSR% =51.6%
|
No significant weight loss
|
Low
|
|
|
Parikshit et al (29)
|
China
|
Breast cancer
|
Female
Balb/C nude mice
|
4−5
|
18 ± 2
|
1.0 × 105 4T1 cells, SC, left armpit
|
every 3 days with 6 times, iv
|
Saline
|
_
|
DSF 15 mg/kg DSF-NLC 15 mg/kg TPGS-DSF-NLC 15 mg/kg
|
TGI%=8.49%. TGI%=29.2% TGI%=48.24%
|
No noticeable body weight loss
|
Safety
|
|
|
|
Ji et al (30)
|
China
|
Breast cancer
|
Female
Balb/C nude mice
|
_
|
20 ± 2
|
8.0 × 105 4T1 cells, SC, right flank
|
every days with 2weeks, iv or every day with 2weeks, ig
|
Saline
|
PTX (8mg/kg )
TSR%=55.01%
|
DSF 20 mg/kg ig DSF-NSps 20 mg/kg ig DSF-NSps 20 mg/kg iv DSF-NSps 10 mg/kg iv DSF-NSps 5 mg/kg, iv
|
TSR%=0% TSR%=59.03% TSR%=80% TSR%=75.86% TSR%=69.21%
|
Weight increased slightly
|
_
|
|
|
|
|
|
Zhou et al (37)
|
China
|
Liver cancer
|
KunMing mice
|
5–6
|
_
|
1.5 × 107 H-22 cells, SC, left axilla
|
every 3 days with 4 times, iv
|
Saline
|
5-FU
(20 mg/kg )
TIR% =47.4%
|
DSF NPs 3 mg/mL DSF NPs 40 mg/kg + Cu(OI)2-S 0.3 mg/kg DSF NPs 40 mg/kg + Cu(OI)2-L 0.3 mg/kg
|
TIR% =26.8% TIR% =35.5% TIR% =50.3%
|
_
|
_
|
|
|
|
Tao et al (31)
|
China
|
Breast cancer
|
Female
Balb/C nude mice
|
_
|
20 ± 2
|
3.0 × 106 4T1 cells, SC, right flank
|
every 2 days with 4 times, iv
|
Saline
|
DOX
(5 mg/kg )
TIR% =68.27%
|
DSF 5 mg/kg DOX 5 mg/kg +DSF 5 mg/kg Co-NPs (DOX 5 mg/kg + DSF 5 mg/kg)
|
TIR% =34.81% TIR% =80.92% TIR% =89.27%
|
No significant difference in body weight change
|
Safety
|
|
|
|
Song et al (32)
|
China
|
Lung cancer
|
Female
Balb/C nude mice
|
6
|
20.0
|
2.0 × 106 A549DDP cells, SC, right flank
|
every 2 days with 4 times, iv
|
Saline
|
_
|
PGA-CisPt 5.0 mg/kg PGA-CisPt 5.0 mg/kg+ NPs-DSF 10.mg/kg
|
TSR%=45.6% TSR%=75.4%
|
No body weight changes
|
Safety
|
|
|
Hamidreza et al (33)
|
Iran
|
Breast cancer
|
Female
Balb/C nude mice
|
5
|
_
|
1.0 × 106 4T1 cells, mammary fat pad
|
2 weeks, iv
|
Blank NPs
|
_
|
DFS 10 mg/kg DS-P-NPs 10 mg/kg DS-PPF-NPs 10 mg/kg
|
TSR%=17.07% TSR%=66.67% TSR%=75%
|
DS-P-NPs, DS-PPF-NPs groups more reduction weight than the DSF
|
No sign
|
|
|
|
Song et al (34)
|
China
|
Breast cancer
|
Balb/C mice
|
5-6
|
_
|
2.0 × 106 4T1 cells, SC, right flank
|
every 2 days with 6 times, iv
|
Saline
|
_
|
DSF 15 mg/kg NP4/5/1 15 mg/kg
|
TSR%=0
TSR%=43.2%
|
No obvious body weight loss
|
Safety
|
|
|
Jennifer et al (38)
|
USA
|
Breast tumor
|
Female
SCID mice
|
_
|
_
|
1.0 × 106 SUM149 cells, SC, flank
|
daily, iv
|
Vehicle
|
_
|
DSF 50 mg/kg DSF 50 mg/kg + Cu 0.5 mg/kg
|
TIR% =75% TIR% =84%
|
No noticeable body weight change
|
_
|
|
|
Choi et al (35)
|
Korea
|
Atypical teratoid/rhabdoid tumors
|
Female
Balb/C nude mice
|
7
|
_
|
1.0 ×104 AT/RT cells, SC, _
|
every 5
consecutive days with 3weeks, ip
|
DMSO
|
_
|
DSF 100 mg/kg
|
TSR%=72.25%
|
_
|
No major
|
|
|
Vino et al (36)
|
China
|
Malignant Pleural Mesothelioma
|
Female
Balb/C nude mice
|
5
|
_
|
0.5 × 106 AB12 cells, SC, right flanks
|
daily with 17 days, ip
|
Vehicle
|
_
|
DSF/Cu 50 mg/kg
|
TSR%=71.5%
|
Weight of DSF-Cu group was 75% lower than that of vehicle group
|
_
|
|
|
|
Abbreviations: DOX, doxorubicin; Cis, cisplatin; 5-Fu, 5-fluorouracil; V, Volum; L, Length=longest diameter of the tumor; W, Width=shortest diameter of the tumor; SC, subcutaneous; iv, intravenous injection;TGI, tumor growth inhibition rate; TGI%= [(Vc1-Vt1)/(Vc0-Vt0)]×100%; TIR, tumor inhibition rate; TIR% = [(Vc-Vx)/Vc] ×100%; TSR, tumor suppression rate ; TSR% = [(Vc-Vx)/Vc] ×100%; Vc, mean tumor volume of the negative control group; Vt, mean tumor volume of certain administration group; Vc1, mean tumor volume in the negative control group at the time of tumor extraction; Vt1, mean tumor volume in the treatment groups at the time of tumor extraction; Vc0, mean tumor volumes in the negative control group; Vt 0, mean tumor volumes in the treatment group; NPs, nanoparticles; NSps, nanosuspensions; NLC, nanostructured lipid carriers; TPGS, D-alpha-Tocopheryl polyethylene glycol succinate; PNpL-DSF/Cu, Polymeric Nanoparticles Loading Copper(II) Diethyldithiocarbamate (DSF/Cu 1:1) ;Cu(OI)2-S: Administration of copper oleate solution; Cu(OI)2-L: Administration of copper oleate liposome; NP4/5/1, the feed ratio of mPEG-PLGA/PCL/DSF was 4/5/1 in mass; PLGA, Poly (lactide-co-glycolide) ; PEG, Poly(ethyleneglycol); mPEG-PLGA,methoxy poly(ethylene glycol)-b-poly(lactide-co-glycolide); PCL, polycaprolactone; DCC, N,N′ -Dicyclohexylcarbodiimide; DCM, Dichloromethane NHS, sulfo-N-hydroxysuccinimide; DS-PPF-NPs, disulfiram encapsulated PLGA PEG-folate NPs; DS-P-NPs, disulfiram encapsulated PLGA NPs.
Of 11 animal studies, Balb/C nude mice were utilized in nine (Peng et al. 2019; Banerjee et al. 2019; Ji et al. 2019; Tao et al. 2018; Song et al. 2016; Fasehee et al. 2016; Song et al. 2015; Choi et al. 2015; Cheriyan et al. 2018), whereas the remaining studies used KunMing (Zhou et al. 2018) or female SCID (Allensworth et al. 2018) mice. Ten studies used subcutaneous tumor models by injecting cancer cell lines (Peng et al. 2019; Banerjee et al. 2019; Ji et al. 2019; Tao et al. 2018; Song et al. 2016; Song et al. 2015; Choi et al. 2015; Cheriyan et al. 2018; Zhou et al. 2018; Allensworth et al. 2015), and one study used an in situ tumor model (Fasehee et al. 2016). Eleven studies had assessed the dimensions of tumor volume (V) using the same formula (V= 0.5 × length × width2) (Peng et al. 2019; Banerjee et al. 2019; Ji et al. 2019; Tao et al. 2018; Song et al. 2016; Fasehee et al. 2016; Song et al. 2015; Choi et al. 2015; Cheriyan et al. 2018; Zhou et al. 2018; Allensworth et al. 2015), nine studies assessed changes in body weight in mice (Peng et al. 2019; Banerjee et al. 2019; Ji et al. 2019; Tao et al. 2018; Song et al. 2016; Fasehee et al. 2016; Song et al. 2015; Cheriyan et al. 2018; Allensworth et al. 2015), and six studies contained data regarding the toxicity of DSF (Peng et al. 2019; Banerjee et al. 2019; Song et al. 2016; Fasehee et al. 2016; Song et al. 2015; Choi et al. 2015). In addition, eight of the animal studies used DSF by re-synthesizing the molecule with nanomaterials ((Peng et al. 2019; Banerjee et al. 2019; Ji et al. 2019; Tao et al. 2018; Song et al. 2016; Fasehee et al. 2016; Song et al. 2015; Zhou et al. 2018).
The three human studies included participants with differing characteristics and cancer types. All three clinical trials investigated DSF as a combination therapy with chemotherapy or/and radiation therapy (Huang et al. 2019; Huang et al. 2018; You et al. 2019), while two studies reported on adverse events (Huang et al. 2019; Huang et al. 2018).
Table 3
Eeffects of disulfiram on PFS and OS from human studies
Reference
|
Country
|
Study design
|
Study participants
|
Study protocol
|
OS
|
PFS
|
Adverse events
|
Huang, et al
(39)
|
USA
|
Phase II,
open-label, single-arm study
|
Recurrent GBM who had developed unequivocal progression after RT and concurrent TMZ as per "the RANO criteria while receiving adjuvant TMZ or within 3 months from the last dose of TMZ”
|
DSF 80 mg and Cu Gluconate1.5 mg TID by mouth approximately 4–8h
apart.
|
7.1 months
(95% CI: 5.8–8.5)
|
1.7 months
(95% CI: 1.4–1.9)
|
Nausea/vomiting (17%) followed by dizziness (9% grade ),Only one patient (4%) had a possible DLT with grade three elevated alanine transaminase on day 31, which required study therapy to be held. The liver function test subsequently recovered after 4 weeks.
|
Huang, et al
(40)
|
USA
|
Phase I,
open-label, single-arm, single-institution study
|
Adjuvant TMZ in newly diagnosed adult GBM patients after standard chemoradiotherapy
|
7 patients at DSF 500 mg per day 5 patients at DSF 1000 mg per day, 6 patients at DSF 500 mg per day with Cu 2 mg
|
14.0 months
(95% CI 8.3–19.6)
|
4.5 months
(95% CI 0.8–8.2)
|
one with delirium after 1.6 months (without Cu),one with motor neuropathy after 2.6 months (without Cu),one with diarrhea and nausea after 0.5 months (with Cu),All symptoms resolved shortly after dose reduction.
|
Nechushtan, et al (41)
|
Israel
|
phase II, multicenter randomized double-blinded study
|
Newly diagnosed NSCLC patients were recruited. Patients with either stage IV or what was considered at the time “wet IIIb” (since 2009, these patients have been considered stage IV) were recruited. The patients were treated with only chemotherapy, and none were treated with either surgery or chemoradiation.
|
controls: six cycles of cisplatin and vinorelbine (plus placebo tablets),
experimental groups: the same plus disulfiram (40mg three times daily).
|
10.0 versus 7.1 months
|
5.9 versus 4.9 months
|
_
|
Abbreviations: GBM, glioblastoma; NSCLC, non-small cell lung cancer; TMZ, temozolomide; TID, three times per day; DLT, dose-limiting toxicity; RANO, Radiologic Assessment in Neuro-Oncology.
|
Outcomes
Three cell lines and one animal study showed that treatment with DSF as a single agent induced apoptosis and increased the rate of tumor inhibition (Sharma et al. 2016; Rezkk et al. 2013; Dastjerdi et al. 2014; Choi et al. 2015). Although the sensitivity between the various cell lines varied, dose-dependency was consistently observed.
The concentration-dependent increase in apoptosis and tumor inhibition rates was augmented by a combination therapy of DSF adding metal ions [copper (Cu), silver (Ag)] in 10 in vitro (Wu et al. 2019; Yang et al. 2016; Kim et al. 2016; Wu et al. 2018; Chen et al. 2018; Butcher et al. 2018; Guo et al. 2019; Yang et al. 2017; Han et al. 2013; Nechushtan et al. 2015) and three in vivo studies (Cheriyan et al. 2018; Zhou et al. 2018; Allensworth et al. 2015). The synergistic effect of Cis, DOX, TMZ, PTX, Gy, and DSF in induced apoptosis was significantly higher than that of DSF or Cis or DOX or TMZ or Gy alone (Yang et al. 2019; Wu et al. 2019; Yang et al. 2016; Albers et al. 2014; Zhao et al. 2015; Nechushtan et al. 2015) Tumor cell growth was significantly inhibited when DSF, chemotherapy, and radiation therapy were used simultaneously, as shown in the examined in vivo studies (Ji et al. 2019; Tao et al. 2018;. Choi et al. 2015; Zhou et al. 2018).
Compared with free molecule, DSF encapsulated with nanomaterials significantly induced selective death-dependent apoptosis, especially in acidic conditions (pH = 6.5) in cancer cell lines. Eleven animal studies demonstrated that DSF modified by particular nanomaterials increased the tumor inhibition rate and that the anticancer activity was more obvious when chemotherapy (Cis) was combined with nanoencapsulated DSF (Song et al. 2016).
Changes in body weight during the whole study period were analyzed in nine animal studies. With the exception of three reports of weight changes in DSF-treated or DSF-modified groups (Ji et al. 2019; Fasehee et al. 2016; Cheriyan et al. 2018), other studies recorded that there was no noticeable body weight loss after DSF treatment or no significant difference in body weight changes across different groups (Peng et al. 2019; Banerjee et al. 2019; Ji et al. 2019; Tao et al. 2018; Song et al. 2016; Song et al. 2015; Cheriyan et al. 2018; Allensworth et al. 2015), which indicated that there was no major toxicity of DSF (Peng et al. 2019; Banerjee et al. 2019; Song et al. 2016; Fasehee et al. 2016; Song et al. 2015; Choi et al. 2015).
Many clinical trials have mentioned the use of DSF for solid tumors (www.clinicaltrials.gov). One study clearly analyzed the difference in PFS (5.9 versus 4.9 months) and OS (10.0 versus 7.1 months) between control and experimental groups (Nechushtan et al. 2015). PFS and OS both improved in the experimental groups. Two studies described PFS and OS of the entire research cohort, and the treatment efficacy seemed to be in contrast to historical data (Huang et al. 2019; Huang et al. 2018). Our systemic review included two single-arm trials in glioblastoma (GBM) patients and a randomized controlled trial in NSCLC patients. Although the two single-arm clinical trials did not compare treatment with a control group, positive effects were observed; e.g., a 40-year-old woman with unmethylated isocitrate dehydrogenase wild-type GBM had good health without any signs of tumor recurrence 33 months after study initiation.
Among the reported adverse effects, none were serious, and they were of Grade 2-3. Adverse effects were reported in two studies and included diarrhea, nausea, dizziness, vomiting, motor neuropathy, and elevated alanine transaminase levels. Symptoms resolved quickly when the dose was reduced (Huang et al. 2019; Huang et al. 2018).
All three studies show that DSF is safe and seems to prolong survival of cancer patients. Because of individual differences in patients, the response to DSF was also varied (Huang et al. 2019; Huang et al. 2018; Nechushtan et al. 2015) .The optimal concentration and sensitivity type should be further explored by in vitro and animal studies.