5. Therapeutic Benefits of Combining Jasmonates with Anti-Cancer Drugs
In addition to the fact that jasmonates induce apoptosis in tumor cells, they can also be combined with other anti-tumor agents to achieve synergistic anti-tumor effects. In fact, many modern chemotherapy procedures use multicomponent combinations of drugs that allow for lower doses to be administered, can reduce undesirable side effects and even overcome drug resistance
[20]. Therefore, studies have been carried out to evaluate the combination of the effects of MJ and various other anticancer agents
[33] that are routinely used in clinical practice: BCNU (carmustine), cisplatin, paclitaxel (taxol)
[34] and doxorubicin (adriamycin) or 3-bromopyruvate (3-BrP) ().
Table 1. Effect of MJ combined with other anticancer agents.
3-BrP—3-bromopyruvate; BCNU—1.3-bis-(2-chloroethyl)-1-nitrosourea; 2DG—2-deoxy-D-glucose; IAP—inhibitors of apoptosis; MJ—methyl Jasmonate; POH—perillyl alcohol; Smac7N—a peptide that contains the N-terminal seven residues of smac; TNFR1—tumor-necrosis factor receptor-1; TRAIL—tumor necrosis factor- (TNF-)related apoptosis-inducing ligand.
The interactions of these combination drugs have been observed in many cell lines of malignant tumors such as: breast, lung, prostate and pancreatic cancer as well as leukemia
[40], where MJ drastically reduced the IC
50 values of the used chemotherapeutic drugs, while reducing of side effects of these drugs. The combination of MJ (0.1 nM) and BCNU (carmustine) therapy (1, 10 and 25 µg/mL—PaCa-2 cell; 2.5 and 5 µg/mL—BCL1 cell) had an adverse effect on pancreatic cancer cells (PaCa-2; BCL1) causing their apoptosis, which was not observed with BCNU alone. It follows that the influence of BCNU on mitochondria
[35] makes them hypersensitive to MJ, resulting in over-additive cytotoxic effects. Another study also showed a positive effect of MJ together with perillyl alcohol (POH), which increased the cytotoxicity of cisplatin in breast cancer cells (MDA-MB-231, MDA-MB-435, MCF7)
[36].
The combination of MJ (0.5–3 mM) and 2DG (2-deoxyglucose, glycolysis inhibitor) (1 and 2 mM) also resulted in a synergistic cytotoxic effect on tumor cells (sarcoma SaOS-2; MCA-105), possibly due to the interaction of both MJ-induced oxidative phosphorylation of ATP biosynthesis and 2DG-induced ATP glycolysis
[22][37]. Most importantly, in vivo experiments have shown that the combination of MJ and doxorubicin has a synergistic effect on mouse leukemia (BCL1)
[22]. Moreover, pre-incubation with MJ (0.5 mM), at non-cytotoxic concentrations, may sensitize colorectal cancer (CRC) cells to ligand-induced apoptosis, inducing TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) (100–200 ng/mL), resulting in synergistic cell death through enhanced caspase activity
[42][38].
TRAIL receptors are highly expressed in primary tumors and various tumor cell lines
[43], which makes this pathway of cytotoxicity very specific for neoplastic cells while sparing most of the normal cells. Therefore, TRAIL-induced cell apoptosis is a very attractive potential target of anti-cancer therapy
[42]. TRAIL, induced by MJ, mediates the reduction in survivin, a member of the Inhibitors of Apoptosis Proteins family (IAP). This study also shows that MJ, by inhibiting transcription, influenced the signal transduction pathways, resulting in a reduction in survivin mRNA
[20]. Nevertheless, many tumor cells are intrinsically resistant to TRAIL-induced apoptosis. Therefore, the results of synergistic cell death achieved by the combination of MJ and TRAIL, through bypassing the TRAIL resistance barrier, have great potential in tumor therapy as both agents are highly selective for tumor cells.
Moreover, studies on prostate (PC-3) and breast cancer cell lines (MDA-MB-435) showed that treatment with jasmonates resulted in increased expression of TNFR1 and caspase-8 and caspase-3 activation
[22], showing that jasmonates can act directly on the extrinsic apoptotic pathway in addition to intrinsic mitochondrial apoptotic pathway. Additionally, the IAP antagonist, an N-terminal peptide consisting of seven Smac residues (SmacN7), synergistically significantly increased MJ-induced cytotoxicity in human cancer cells, but not in normal epithelial cells, and acted simultaneously through caspase-9 dependent and independent pathways
[39][44]. These findings suggest that inhibition of IAP may facilitate MJ-induced cytotoxicity and may be of advantageous value for the further development of jasmonate-based chemotherapy.
MJ (0.5–3 mM) also increased the effectiveness of therapy with the use of 3-BrP (12.5; 25; 50; 100; 200; 400 μM; IC
50 value was 70 μM). This polytherapy was more effective than monotherapy with 3-BrP, MJ, and also surprisingly with cyclophosphamide as a routine treatment for breast cancer in tumor bearing mice, as observed by reducing tumor volume and increasing the percent inhibition of tumor growth. Moreover, the applied therapy had no appreciable side effects on the kidneys, liver, immune system and body weight
[40].
Recently, MJ has also been shown to be effective in cooperating with cisplatin and radiotherapy in the treatment of cervical cancer cells by significantly reducing the doses of radiation and cisplatin required to inhibit these cells’ survival
[22]. This study showed, for the first time, that alpha radiation selectively reduces cell viability and cervical cancer cell survival, and that alpha radiation also works with MJ in reducing cell viability, as shown in some of the cervical cancer cell lines used (SiHa, CaSki, HeLa and C33A)
[41]. In addition, MJ can be administered along with conventional X-ray (0.25–3 Gy) and cisplatin therapies, increasing their cytotoxic efficacy while lowering the dose, avoiding possible side effects.