2.1. Phytochemicals used as adjuvant for chemotherapy
Despite its effectiveness, conventional chemotherapy has may side
effects. Approaches focusing on the combinational efficacy of promising
dietary phytochemicals can be efficacious in cancer chemoprevention.
Various phytochemicals which have increased the efficacy of
chemotherapeutic drugs are discussed below and shown in Table. 2.
Apigenin is a natural plant flavone commonly found in fruits and
vegetables like grapefruit, orange, onion, zlicorice root etc (Shuklaet al. , 2010). Apigenin treatment increased the susceptibility of
HNC cells to chemotherapy as it enhanced the cytotoxicity of Cisplatin
and 5-Fu to SCC25 cells (Chan et al. , 2012). Betulinic acid also
showed additive effects along with cisplatin to inhibit the growth of
HNC. Good bioavailability & the good safety profile of Caffeic Acid
Phenethyl Ester [CAPE, a component of honey beehive] makes it safe
to use through oral route and an ideal candidate for adjuvant therapy.
CAPE can be applied daily for long duration as a topical cream or mouth
wash for regression of oral cancer. CAPE along with 5-fluorouracil shows
additive inhibitory effect on proliferation of TW 2.6 an OSCC cancer
cell line and decreases undesired side effects and other uncomfortable
symptoms in patients due to 5-fluorouracil. CAPE treatment inhibits both
total abundance & phosphorylation of NF-κB at Serine 536 in TW 2.6
cells (Kuo et al. , 2013). Another flavonoid Genistein also showed
synergistic effects with cetuximab via inhibition of EGFR signaling
pathway both in in-vitro in oral cancer cells HSC-3 and KB as
well as in in-vivo (Park et al. , 2010).
EGCG also enhanced the cisplatin-mediated chemosenstivity by decreasing
the ABCG2 and ABCG2 transporter genes (reputed molecules of treatment
resistance of CSCs). Combination of EGCG along with cisplatin
significantly inhibited the tumor formation and induced apoptosis in
xenograft nude mice model (Lee et al. , 2013).
Guggulsterone an important phytosterol isolated from the gum resin of
the Commiphora mukul plant and shows anti-inflammatory activity
by inhibiting inducible nitric oxide synthetase (iNOS) (Meselhy, 2003;
Singh et al. , 2003). Gugglesterone was found to enhance the
efficacy of cisplatin, erlotinib and cetuximab in HNC cell lines as well
as in in-vivo xenograft mice model (Leeman-Neill et al. ,
2009).
Honokiol (HNK) is another active compound present in leaf and bark ofMagnolia officinalis which has shown chemopreventive and
chemotherapeutic effects in many tumor models like breast, melanoma,
prostrate and skin (Hahm et al. , 2008). HNK minimized the
chemoresistance by downregulating the P-glycoprotein expression in MDR
SCCHN cells. It arrested cell cycle and induced apoptosis via locking of
survival signals including PI3K/Akt & Mcl-1 and showed synergistic
effect with taxol (Wang et al. , 2007). It also enhanced the
efficacy of Paclitaxel in multi drug resistant [MDR] HNC cells
[KB-8-5, KB-V1 & KB-C1]. HNK induced mitochondrial & death
receptor dependent apoptosis in MDR KB cells via inhibiting the
EGFR-STAT3 pathway (Wang et al. , 2014). In another study HNK
decreased the self-renewal & survival of OCSCs dose dependently via
downregulation of ALDH1 & CD44.Thus HNK potentiates the effect of
cisplatin via reducing the stemness characteristics (Chang et
al. , 2018). HNK is aphytochemicals which can be used with different
chemotherapeutics drugs like paclitaxel, Taxol, Cisplatin to sensitize
chemoresistant HNC and may give a better therapeutic opportunity for HNC
cure.
Benzylisothiocyanate (BITC) is an Isothiocyanate (ITC) of specific
attraction for anticancer therapy, due to its capability to inhibit cell
growth & induce apoptosis in many types of cancers including HNC (Wuet al. , 2009). BITC sensitized the HN8, HN12 and HN30 cells to
cisplatin treatment. Combined treatment reduced cell viability
significantly than either treatment alone. It also inhibited expression
and regulated the localization of EMT marker vimentin (Wolf et
al. , 2014).
Lupeol is a pentacyclic triterpene, commonly found in olive, green
pepper, mango, white cabbage, strawberry, and grapes and posses many
pharmacological activities including anti-oxidant, anti-inflammatory,
anti-angiogenic and anticancer properties (Liu et al. , 2021).
Lupeol was found to re-sensitize primary HNC tumor sample, already
treated with cisplatin. Synergistic chemosensitization effect with
cisplatin was observed with high NF-ĸB activity in-vitro .
2mg/animal dose of lupeol significantly decreased the tumor volume and
also suppressed local invasion and nodal metastasis in an Orthotopic
Nude Mouse Model (Lee et al. , 2007). Luteolin also showed
synergistic effect with paclitaxel in HNC by enhancing inhibition of
tumor growth (Yang et al. , 2008).
Quercetin and cisplatin when given simultaneously showed synergistic
effects and allowed the use of less toxic doses of chemotherapy for
management and treatment of HNC (Sharma et al. , 2005). A
xenographic study also showed positive effect when combination of
quercetin and cisplatin was given and an improved prognosis was observed
in OSCC patients (Chen et al. , 2012b).
Resveratrol a phytochemical present in red wine showed synergistic
effect with various cancer therapeutic regimes in head and neck cancer.
Quan et al (2009) reported that resveratrol shows synergistic effect
with paclitaxel as a result of downregulation of the expression of
hypoxia inducible factor 1alpha [HIF-1α], multidrug resistance gene
1 (mdr1), multidrug resistance-associated protein 1 (MRP1) and increased
the apoptotic rate in CNE2 nasopharyngeal carcinoma cell line (Quanet al. , 2009). Resveratrol also showed synergistic effect with
Taxol and inhibited the growth of human laryngeal carcinoma cell line
Hep-2. Apoptosis was induced via increase level of Bax, PARP, TRIB3,
caspase-3,8 and downregulating Bcl-2 and XIAP (Lu et al. , 2016).
Salvianolic acid B [Sal-B] is a promising anticancer agent in HNC.
Zhao et al (2010) studied the combination effect of Salvianolic acid B
with low doses of celecoxib in 4 HNC cell lines [JHU-013, JHU-06,
JHU-022, & JHU-011]. The anticancer efficacy was greatly increased in
JHU-013 and JHU-022 cell line when combination was given. 40mg/kg/day of
Sal-B & 2.5mg/kg/day of celecoxib significantly reduced the JHU-013
xenograft tumor growth as compared to mice treated with full dose of
celecoxib or Sal-B alone.
Silibilin (SB) a phytochemical from milk thistle plant also shows
synergistic activity with various chemotherapeutic drugs like
5-fluorouracil, doxorubicin, etc to prevent the renewal and growth in
HNC-TICs. Silibilin suppress the proliferation of both OECM1 and SAS
cells and downregulates the CD133 positivity, ALDH1 activity,
self-renewal property, stemness signatures expression and
chemoresistance in dose-responsive manner. It also decreased the mRNA
and protein expression of Nanog, Oct-4 and nestin in both these HNC-TICs
(Chang et al. , 2015).
The combination of TQ, with Cisdiamminedichloridoplatinum (II) (CDDP)
induced greater cytotoxicity in UMSCC-14 cell lines as compared to
normal oral epithelial cells OEC. Both TQ and CDDP show synergistic
effect on UMSCC-14 and OEC via change in expression levels of Bcl-2, p53
and caspase-9 protein resulting in increased apoptosis (Alaufi et
al. , 2017).