Ekstrak Kurkuminoid

1. Riki-Rki,2017 http://journal.uta45jakarta.ac.id/index.php/INRPJ/article/view/822

Penggunaan kurkuminoid temulawak menjadi salah satu alternatif pengobatan kanker serviks karena
banyak penelitian menunjukkan bahwa kurkuminoid mampu menghambat pertumbuhan berbagai jenis
sel kanker. Kurkuminoid digabungkan ke dalam sistem pembawa obat nanopartikel lemak padat untuk
mengatasi bioavailabilitasnya yangrendah. 

Berdasarkan hasil uji MTT, sediaan nanopartikel ekstrak kurkuminoid memiliki kemampuan
penghambatan pertumbuhan sel HeLa yang lebih tinggi dibandingkan dengan ekstrak

Data ini menyarankan bahwa nanopartikel ekstrak kurkuminoid dapat menjadi kandidat potensial obat
antikanker serviks.

2. https://juke.kedokteran.unila.ac.id/index.php/agro/article/viewFile/2422/pdf

Mekanisme dalam menghambat tumorigenesis oleh kurkumin bervariasi dan melibatkan kombinasi
antiinflamasi, antioksidan, imunomodulator, proapoptotik, dan sifat anti-angiogenik melalui efek
pleiotropik pada gen dan jalur pensinyalan sel pada berbagai tingkatan baik secara intrinsik maupun
ekstrinsik. Efek genotoksisitas/antigenotoksik kurkumin pada sel kanker yang terpapar cisplatin
menunjukkan bahwa, kurkumin secara signifikan mengurangi frekuensi total mikronukleus yang
diinduksi oleh cisplatin. Selain dapat bekerja secara mandiri, kurkumin juga mampu bekerja bersama
dengan agen anti-kanker lainnya.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022204/

Inhibition expression of viral oncoproteins of E6 and E7 Divya CS,

Pillai MR.
Antitumor action of curcumin in human papillomavirus associated cells
involves downregulation of viral oncogenes, prevention of NFkB and AP-
1 translocation, and modulation of apoptosis.
High-risk human papillomaviruses (HPVs) infection via the expression of
E6 and E7 viral oncoproteins has a critical role for development of
cervical carcinoma. Curcumin showed the inhibitory activity against the
expression of E6 and E7 genes of HPV-16 and HPV-18 as two main highly
oncogenic human papilloma viruses [37]. The transcription factor AP-1
is a critical factor for transcriptional regulation of high-risk HPVs such as
HPV-16 and HPV-18. Curcumin downregulates the AP-1 binding activity
in HeLa cells with decreasing effect on the transcription of HPV-18 [38].
The results showed that curcumin through apoptosis modulation and
also prevention of NFκB and AP-1 translocation associated with
downregulation of viral oncogenes and decreasing the transcription of
HPVs can be a good candidate for the management of highly oncogenic
HPV infections 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6270789/
Curcumin is a symmetric molecule, also known as diferuloyl methane.
The IUPAC name of curcumin is (1E,6E)-1,7-bis(4-hydroxy-3-
methoxyphenyl)-1,6-heptadiene-3,5-dione, with chemical formula
C21H20O6, and molecular weight of 368.38. It has three chemical entities in
its structure: two aromatic ring systems containing o-methoxy phenolic
groups, connected by a seven carbon linker consisting of an α,β-
unsaturated β-diketone moiety [3,4,5,6,33]. The chemical structure of
curcumin is given in Scheme 2.
Gold nanoparticle-based curcumin formulations have been
prepared and reported recently. Gold nanoparticles find application in
biology and medicine, for drug delivery, diagnosis and cancer treatment
[108,109,110,111]. In a simple method, curcumin-gold composites were
prepared by mixing alkaline curcumin solutions with gold salts, where
the ionized curcumin acts both as a reducing agent and also as the
capping agent [108]. In this case, both the phenolic-OH and enolic-OH
donate hydrogen for reduction of Au3+ ions (Figure 3). Such gold-
curcumin conjugates were reported to be hemocompatible and non-
toxic. Singh et al. [109] also prepared gold-curcumin conjugates by
mixng the gold salt with curcumin at high temperature. Such conjugates
have been reported to exhibit antixodiant activity by DPPH assay. In
another study, curcumin was first conjugated to hyaluronic acid (HA)
and this conjugate is treated with gold salt, where HA acted as the
reductant [110]. These gold-HA-curucmin composites were
biocompatible and exhibited more cytotoxicity in cancer cell lines than
pure curcumin. Other gold-curcumin composites were also prepared by
conventional methods employing sodium citrate as reducing agent and
polymeric systems as capping agents. Such systems can also be
employed for the delivery of curcumin

Recently magnetic nanoparticles (MNP) are attracting the attention of

researchers. MNP, mostly of iron oxide, are used as drug delivery
systems and MRI contrasting agents [114,115,116,117]. They can be
targeted magnetically and applied for local hyperthermia. Recently a few
reports on preparation and charactirisation of MNP-curucmin conjugates
are reported [114,115,116,117]. They have also been evaluated for
diagnosis and anticancer activity. MNP is coated with pluronic polymers
or other biopolymers to load hydrophobic drugs like curcumin (Figure
4). MNP-curucmin can be magnetically and selectively accumulated in
cancer cells. In one such study, Yellapu et al. [115,116,117] prepared
curcumin-loaded MNPs modified with cyclodextrin and reported
inhibition effects in ovarian, breast, and prostate cancer cells and also in
human pancreatic xenografts. MNP-curucmin has been found to cause
apoptosis in MDA-MB-231 breast cancer cell lines along with loss of
mitochondrial membrane potential and increased ROS production. MNP-
curucmin improved the serum bioavailability by 2.5-fold. The
formulation showed good MRI imaging characteristics. MNP
formulations along with porous silica nanoparticles have also been
employed to encapsulate curcumin, for efficient delivery of curcumin.
Due to their selective accumulations and ability to cause hyperthermia,
MNP-curcumin with suitable modifications are attracting the attention of
many researchers for specific application in cancer therapy and
diagnosis.

https://www.mdpi.com/1422-0067/21/24/9435
One method of overcoming low bioavailability is to decrease the size of the bioactive agent, therefore
increasing its solubility; this has been the focus of improving the preparations of curcumin over the past
years [15]. A limitation to producing ingestible medications is the solvents in which they are prepared with.
Low-crystallinity nanoparticles are the most recent “green” solutions to the bioavailability issues of
curcumin. Traditionally, low-crystallinity nanoparticles were generated by exposure to various toxic
solvents, such as chloroform, or via the formation of cyclodextrin complexes, which would limit medical
application. A novel method of generating low-crystallinity curcumin nanoparticles was formulated by
integrating low-crystallinity curcumin into a nanoporous starch aerogel (NSA). After incorporation into the
NSA, the curcumin-NSA matrix was subjected to drying by exposure to supercritical carbon dioxide.
Through precipitation by pressure reduction of gas-expanded liquid (PPRGEL), spherical curcumin
nanoparticles can subsequently form due to hydrophobic effect, with particle size averaging from 66 to 71
nM depending on temperature. At room temperature curcumin NSA nanoparticles increased the
bioavailability of curcumin by 173-fold (0.4% curcumin vs. 69.1% low-crystallinity curcumin nanoparticles)
[15]. Poly-lactic-co-glycolic acid (PLGA) nanoformulated curcumin has been shown to have three to four
times greater concentration and longevity in CNS tissue at similar oral doses when compared to standard
curcumin preparations in a murine model [16]. Nanosuspension preparations of curcumin increase
saturation solubility and dissolution velocity by the creation of pure drug crystals with accompanying
stabilizer, with more modest increases in bioavailability by 4.2-fold [17]. It is important to note that high
drug concentration can be achieved with a relatively low number of stabilizers and this preparation has
been extensively studied via multiple routes of administration including oral, intramuscular, intravenous,
ocular and pulmonary systems [18].

Sreekanth (2011) https://www.jbuon.com/archive/21-5-1050.pdf

The combined treatment of curcumin and paclitaxel induced a synergestic reduction in the tumor
incidence as well as tumor volume of animals compared with the individual treatments of paclitaxel or
curcumin, although curcumin alone could not induce any significant effect at the concentration used.
The results suggested that a suboptimal concentration of curcumin augmented the antitumor action of
paclitaxel by downregulating the activation and downstream signaling of antiapoptotic factors and
survival signals such as NF-κB, Akt and mitogen-activated protein kinases that have significant roles in
proliferation, survival, angiogenesis and metastasis.

https://www.tandfonline.com/doi/full/10.1080/21691401.2018.1442345

Curcumin, an active principle of Curcuma longa, is extracted from the

rhizome. Its therapeutic efficiency has been proved using various in
vitro and in vivo models.

Curcumin has been developed using various techniques, particularly micro

and nanotechnology to improve its stability and bioavailability. This review
focuses on the studies pertaining to the delivery of curcumin in the form of
micro and nanosize formulations for the treatment of a variety of diseases.
Enhanced cellular uptake and increased bioactivity in inducing apoptosis and suppressing proliferation of
tumour cells

Latar Belakang
Belakangan ini, fitofarmaka telah mendapat perhatian sebagai salah satu strategi pengobatan,
termasuk penyakit kanker. Salah satu obat herbal yang telah dilakukan uji coba pada biakan sel
adalah curcumin. Curcumin merupakan ekstrak rimpang yang salah satunya berasal dari kunyit
yang banyak tumbuh di Indonesia.

Riki-Rki,2017 http://journal.uta45jakarta.ac.id/index.php/INRPJ/article/view/822

kemampuan nanopartikel ekstrak kurkuminoiddalam menghambat pertumbuhan sel HeLa lebih tinggi
dibandingkan dengan ekstrak, sejalan dengan hasil uji Brine Shrimp Lethality Test(BSLT)yang
menunjukkan nanopartikel lebih toksik dibandingkan dengan ekstrak. Hal ini disebabkannanopartikel
dapat masuk ke dalam sel membawa ekstrak kurkuminoiddengan mekanisme endositosis.
Nanopartikel diproses melalui interaksi spesifik antara permukaan nanopartikel dan reseptor
permukaan sel yang selanjutnya mengaktifkan berbagai jalur pensinyalan. Selain mekanisme
endositosis, nanopartikel juga dapat masuk ke dalam sel melalui penetrasi bilayer pasif.
Kemampuan nanopartikel untuk melekat dan melewati membran sel bergantung pada karakteristik
fisikokimianya berupa ukuran, komposisi dan muatan permukaannya. Nanopartikel yang ukurannya
kecil (< 200 nm) mudah melewati membran sel, sedangkan yang berukuran besar dapat melewati
membran dengan Indonesia Natural Research Pharmaceutical Journal (Vol. 2, No. 1, Maret–Agus2017)Universitas 17 Agustus
1945 JakartaIssn Online: 2502-8421menginduksi deformasi membran sel (Tsuda et al.,2015

Mekanisme penghambatan ekstrak kurkuminoidtemulawak terhadap sel HeLa belum diketahui.

Namun, penelitian menunjukkan bahwa kurkumin sebagai salah satu komponen ekstrak
kurkuminoidtemulawak sangat berperan dalam meregulasi aktvitas jalur NF-κB dan Akt pada sel
HeLa yang memicu terjadinya proses apoptosis dan menghambat proliferasi sel (Sreekanth et
al.,2011).Mekanisme lain yang mungkin adalah menghambat aktivitas telomerase. Sel kanker
serviks yang diinfeksi HPV diketahui mengekspresikan onkogen E6. Protein E6 menstimulasi
aktivitas enzim telomerase (DeFilippis et al.,2003).Ramachandran et al.(2002)melaporkan bahwa
kurkumin mampu menghambat aktivitas telomerase pada sel kanker payudara MCF-7. Kurkumin
juga diketahui menghambat aktivitas telomerase pada sel neuroblastoma manusia (Aravindan et
al.,2011).Hal ini juga didukung hasil simulasi docking yang menunjukkan kurkumin memiliki interaksi
dengan kestabilan yang baik terhadap enzim 12-lipoksigenase yang berperan pada proses inflamasi
(Syahputra, 2014)

Penggabunganekstrak kurkuminoidke dalam bentuk nanopartikel lipid padat dapat meningkatkan

aktivitas sitotoksiknya
8Indonesia Natural Research Pharmaceutical Journal (Vol. 2, No. 1, Maret–Agus2017)Universitas 17 Agustus 1945 JakartaIssn
Online: 2502-8421terhadap sel HeLa. Nanopartikel dapat menghambat pertumbuhan sel HeLa

https://juke.kedokteran.unila.ac.id/index.php/agro/article/viewFile/2422/pdf

Indonesia merupakan negara yang kaya akan keanekaragaman hayati termasuk tanaman obat, salah
satunya adalah kunyit. Kunyit mudah tumbuh hampir di seluruh wilayah dataran tinggi maupun rendah.
Kunyit juga tumbuh liar di alam maupun ditanam di pekarangan sehingga mudah didapatkan
Penggunaan kunyit (Curcuma longa) di Indonesia selain sebagai rempah penyedap masakan juga
memiliki khasiat sebagai jamu

Curcuma longa Linn. (C. longa), keluarga Zingiberaceae, adalah tanaman asli Asia, terutama India,
Indonesia dan Cina. Rimpang C. longa, juga disebut kunyit, telah lama digunakan sebagai rempah atau
makanan tambahan dan dalam sistem pengobatan tradisional di Asia. Studi tentang fitokimia kunyit
telah mengungkapkan mengandung kurkuminoid dan minyak atsiri sebagai komponen utama. Kurkumin
dan dua turunan demethoxy, demethoxycurcumin dan bisdemethoxycurcumin, adalah kurkuminoids
utama dalam kunyit, yang memiliki aktivitas anti kanker, antiinflamasi, neuroprotektif, anti- Alzheimer
dan anti oksidan.2

Efek anti-tumor dari kurkumin sebagian disebabkan oleh penekanan proliferasi sel, pengurangan beban
tumor dan induksi apoptosis pada berbagai model kanker, baik in vitro dan in vivo. Kurkumin
menghambat beberapa level dalam jaringan transkripsi untuk membatasi proliferasi sel. Dengan cara
menginduksi apoptosis p53 pada berbagai kanker usus besar, payudara, kandung kemih, neuron, paru-
paru, ovarium, sementara penangkapan fase G2/M pada p53 oleh kurkumin telah diamati dalam sel
kanker kolorektal. Lebih jauh lagi, kurkumin menghambat aktivasi EGFR, aktivitas Src, dan menghambat
aktivitas beberapa reseptor nuklir. Kurkumin menunjukkan efek penghambatan pada Cox-2 dan cyclin
D1, yang dimediasi melalui NF-kB, dan membatasi pertumbuhan sel tumor.9

Ukuran Nanopartikel emas

Frontiers | Human Papillomavirus E6 and E7: The Cervical Cancer Hallmarks and Targets for Therapy
(frontiersin.org)
Human papillomavirus (HPV)-induced cervical cancer is a major health issue among women from the poorly/under-
developed sectors of the world. It accounts for a high-mortality rate because of its late diagnosis and poor
prognosis. Initial establishment and subsequent progression of this form of cancer are completely dependent on
two major oncogenes E6 and E7, which are expressed constitutively leading to tumorigenesis. Thus, manipulation
of these genes represents the most successful form of cervical cancer therapy. In the present article, information
on structural, functional, and clinical dimensions of E6 and E7 activity has been reviewed. The genome organization
and protein structure of E6 and E7 have been discussed followed by their mechanism to establish the six major
cancer hallmarks in cervical tissues for tumor propagation. The later section of this review article deals with the
different modes of therapeutics, which functions by deregulating E6 and E7 activity. Since E6 and E7 are the
biomarkers of a cervical cancer cell and are the ones driving the cancer progression, therapeutic approaches
targeting E6 and E7 have been proved to be highly efficient in terms of focused removal of abnormally propagating
malignant cells. Therapeutics including different forms of vaccines to advanced genome editing techniques, which
suppress E6 and E7 activity, have been found to successfully bring down the population of cervical cancer cells
infected with HPV

Additionally, therapeutics using natural compounds from plants or other natural repositories, i.e.,
phytotherapeutic approaches have also been reviewed here, which prove their anticancer potential through E6
and E7 inhibitory effects. Thus, E6 and E7 repression through any of these methods is a significant approach
toward cervical cancer therapy, described in details in this review along with an insight into the signaling pathways
and molecular mechanistic of E6 and E7 action.

Thus, this article tries to encompass all the structural features and the biological functions of E6 and E7 oncogenes along
with its role as a therapeutic target, helping to gather a comprehensive knowledge about E6 and E7.

At the same time, the mortality chart for cervical cancer, however, does not reflect the clinical success of such
vaccination process. The plausible explanation is the unavailability of these vaccines in the underdeveloped countries,
which are the major ones building up the mortality percentage. Moreover, the women from the financially challenged
section of the population are not exposed to enough screening and diagnostic procedures, owing to many socio-cultural
and financial burdens. Since prophylactic vaccines can work only in the early phases, they cannot prevent the
development of cervical cancer in such deprived category of population because of their late diagnosis. The scientific
community is thus focusing on the development of therapies to combat cervical cancer, which have already established
themselves in the women body. This can be facilitated through targeting of the major oncogenes of HPV-driven
carcinogenesis, i.e., E6 and E7. E6 and E7 inhibition can help suppress cervical cancer development even in the advanced
stages.

while E5–E7 are the ones inducing oncogenesis.

while E6 and E7 take in charge of several cellular checkpoints to establish the cancer hallmarks. Hence, this review
focuses on the significance of E6 and E7 oncoproteins only, termed as “oncoplayers” in this review. The late gene coding
section
Throughout the course of infection, E6 and E7 activity are responsible for the multiplication of the viral genome with
the help of the cellular machinery, as revealed by several interactome analyses (Neveu et al., 2012; White et al.,
2012a,b). They can trick the cells to become oncogenic in the process of viral replication. Hence,HPV-mediated tumor
development can be defined as a collateral damage of the viral infection.
E6 dan E7

HPV E6 and E7 viral oncoproteins play the pivotal role in driving the cells toward oncogenesis. In their process of
replicating the viral genome, they can induce all the hallmarks of a cancer cell, i.e., uncontrolled cellular proliferation,
angiogenesis, invasion, metastasis, and unrestricted telomerase activity along with the evasion of apoptosis and growth
suppressors’ activity. Several in vitro and xenograft studies have also shown cancer cells to senesce or undergo apoptosis
in the absence of E6 and E7 activity (Yamato et al., 2008; Jabbar et al., 2009), thus proving the absolute requirement of
E6 and E7 for persistence of HPV-mediated cancer.

E7 was the first oncogene to be discovered, among all the HPV oncogenes. It is a relatively small phosphoprotein of
about 100 amino acids, with three conserved regions 1/2/3 (CR1/2/3). A small portion of CR1 and nearly entire CR2 from
the amino terminal holds sequence similarity with adenovirus (Ad) E1A proteins and large T antigen of SV40 ( Phelps et
al., 1988). The CR2 domain is composed of poorly conserved sequence followed by the CR3 region. The CR3 region at
the carboxyl terminal end is conserved and encodes a zinc finger domain containing two CXXC motifs separated by 29
amino acid residues (Barbosa et al., 1990; McIntyre et al., 1993). It is responsible for the zinc-dependent dimerization and
for mediating E7 interaction with cellular proteins responsible for cell cycle regulation and apoptosis (p21 and pRb;
Ohlenschlager et al., 2006).
On the other hand, E6 is relatively larger protein with 150–160 amino acids coding an 18 kDa protein (Zanier et al.,
2012). It is arranged into two zinc finger binding domains by four Cys-X-X-Cys motifs, which have been found to be
responsible for the oncogenicity of the protein (Nomine et al., 2006). The carboxy terminal domain contains a PDZ-
binding motif responsible for interacting with several cellular proteins (Thomas et al., 2002). Out of all the types of
cellular interactions the oncoproteins undergo, the most significant interaction is the one where E6 can degrade p53 and in
case of E7 is the inhibition of pRb protein.
Besides E6 and E7, E5 also plays a vital role in the process of oncogenesis. E5 is an 83 amino acid hydrophobic
membrane-associated protein associated with endoplasmic reticulum. Initially, E5 from BPV was identified as an
oncogene; later, HPV16 E5 was also proved to be oncogenic, which can induce carcinogenic transformation along with
E6. It is known to induce aberrant cellular proliferation through ligand-mediated activation of EGFR, inhibit apoptosis
through degradation of Fas receptors and prevention of formation of death domain, and help the carcinogenic cells
evade immune trap to progress toward malignancy

E6 and E7 can drive a cell toward malignancy by contributing to the six major hallmarks of cancer, through several
molecular pathways. Detailed insights into the pathways targeted by the oncogenes E6 and E7 to induce each of the
phenotypic hallmark of cancer have been described in this section.

Both E6 and E7 contribute to achieve uncontrolled proliferation through deregulation of growth suppressors. E6
targets an important growth suppressor, p53, while pRb is one of the major targets of E7 among few others.

E6-mediated inhibition of p53 allows several cellular changes to turn a cell oncogenic, one of them being induction of
uncontrolled cell proliferation by evading the cellular checkpoints.

Similarly, E7-mediated inhibition of retinoblastoma protein (pRb) is also a significant step toward achieving
unrestrained cell proliferation. pRb–E2F interaction is a mandatory checkpoint for the cells to travel through G1-S
phase transition. When the cells are not prepared to enter the S-phase, pRb protein remains bound to the E2F family
of transcription factors to prevent them from transcribing the genes required in S phase. In HPV infected cells, E7
targets pRb for ubiquitination, leading to the release of E2F transcription factors, which transcribe cyclin E, cyclin A
and p16INK4A, an inhibitor of CDK4/6, forcing the cells through premature S-phase entry (Boyer et al., 1996). CDK
inhibitor p16INK4A (tumor suppressor protein) is an important

HPV-infected cells show co-expression of E6 and E7, which establishes the perfect environment for sustained
proliferative signaling. The anomalous growth stimulus created by E7-mediated
The HPV oncoproteins disrupt or modulate these pathways to help the cancer cell escape the innate immune protection.
E6 has been found to block apoptosis through both p53-dependent (Garnett and Duerksen-Hughes, 2006) and p53-
independent manner. E6 of not only high risk HPVs but also low risk or cutaneous HPVs can directly interact with BAK
leading to the degradation of BAK in vivo (Thomas and Banks, 1999). Moreover, BAK-mediated intrinsic mode of
apoptosis can also be blocked by E6 through p53-E6AP interaction (Garnett and Duerksen-Hughes, 2006). A study in 1999
showed that when E6 is silenced, p53 levels increase resulting in activation of PUMA promoter, which causes Bax to drive
the cell toward apoptosis through loss in mitochondrial membrane potential (Thomas and Banks, 1999). E6 is also noted
to function independent of p53 as it can also hinder TNF-mediated extrinsic mode of apoptosis through the PDZ domain
of E6, which can bind to TNFR1 and prevent TRADD from interacting with it (Filippova et al., 2002). E6 can interfere with
the programmed pathway of apoptosis through several other targets such as FADD and caspase-8, which are directly
targeted for ubiquitination (Yuan et al., 2012). Another striking activity of E6 was activation of the survivin promoter,
which can also prevent apoptosis from taking place (Borbély et al., 2006). HPV E7 was found to have no such effect;
instead, it showed minimal pro-apoptotic activity, which was nullified

In HPV-infected cervical cancers, the oncoproteins E6 and E7 manage to express hTERT (human telomerase reverse
transcriptase – the catalytic unit of telomerase enzyme) constitutively to establish replicative immortality. E6 has been
reported to activate the Htert

Phytotherapeutic approach relies on the use of natural products for the treatment of several deadly cancer forms, one
of them being cervical cancer. The many different forms of anticancer drugs used in modern-day chemotherapies are
either directly obtained from natural sources or modified versions of them, including the well-known vincristine,
podophyllotoxin, camptothecin, vinblastine, paclitaxel, docetaxel, homoharringtonine, and so on. In addition to this,
several plant compounds or plant extracts have shown promising anticancer effects in cervical cancer cell lines in vitro
and in vivo. Among them, many different natural compounds were found to directly abrogate HPV-E6/E7 activity,
which have been listed in Table 1. Such compounds are important drug candidates for research since they have the
potential to directly knockdown the oncoplayers and help in cervical cancer regression. Moreover, a series of flavonoids
have been identified that can bind to E6 and inhibit the p53 degradation resulting in decreased viability of HPV infected
cervical cancer cells (Cherry et al., 2013). In addition to luteolin, several novel flavonoids were also identified in the
process with a promising therapeutic role in cervical cancer. Several plant extracts and products like latex from Ficus
carica, seed oil from flax, or the stem extracts of Cudrania tricuspidata also showed anti-oncogenic potential as they
could bring down the expression of E6 and E7 transcripts and proteins, with a concomitant apoptotic conclusion (Kwon
et al., 2016; Deshpande et al., 2019; Ghanbari et al., 2019). The use of natural products promises a comparatively safer
alternative therapeutic approach to cervical cancer. Natural product-based remedy offers easier, abundantly available,
inexpensive method of treatment in comparison to the genome editing technologies or the immunotherapeutic method.
The prophylactic and the therapeutic vaccines, or the T-cell-based therapies, or the several modes of genome editing
techniques are too expensive to be afforded by the financially poor section of population, and the most noteworthy fact
points to these economically backward people as the most commonly targeted group of people with cervical cancer, as
discussed previously.

https://www.tandfonline.com/doi/full/10.1080/21691401.2018.1442345

Toxicity study of curcumin nanocomplex

Extraordinary characteristics, for example increased surface area, of

nanomaterials offer immaculate potentials for therapeutic applications. On
the other hand, it also poses threats because of overwhelming cellular
uptake, possible long-term toxicity due to cumulative retention inside the
cells [63]. Curious to answer the question of curcumin toxicity, the authors
established the indispensable toxicological profiles, genotoxicity assays, of
curcumin nanoparticles using advanced techniques at various injury levels.
Dandekar et al. developed the chitosan nanoparticles, named Eudragit S100
(Evonik Industries, Essen, Germany) and its toxicity was evaluated through
acute-toxicity study, sub-acute-toxicity study (28 d) and various genotoxicity
studies like in vivo micronucleus assay, in vivo chromosomal aberration assay
and in vivo comet assay. It was reported that prepared formulation was
tolerable and safer than the therapeutic dose level in both in vitro and in
vivo conditions [64]. Solubility of curcumin limits its applications for
therapeutics. Curcumin nanosuspension was prepared with solvents of
PVPK30 and SDS and curcumin released 84% within 34 h and it showed
higher toxicity as well. Pharmacokinetic studies showed that CU-NS quickly
reached the tissue organs, suggesting that the formulation is effective;
however, toxicity of SDS remains questionable when translated [65]. No
other study showed about the toxicity of curcumin or its derivative molecules
with or without other compounds and hence further studies is needed to
confirm the previous findings.

One of the greatest problems in the conversion of herbal medicine into

commercial products is the lack of fastness in the healing process, side
effects due to impurity and lack of understanding at molecular level
interactions with cellular proteins and consequent elevation and
suppression of genes responsible for curing. There have been a number
of studies for the improvement of bioavailability with various
techniques and carrier compounds (1); however, it is difficult to
determine the concentration of curcumin in vivo. Elaborate studies with
curcumin nanoparticles are required in the preclinical and clinical
levels. Quantitative estimation of clinical parameters both in
biochemical and molecular levels are required for comparison with
different models, mode of injection and various nanomaterials which
will give a direction on the amelioration of disease conditions. As well,
the toxicity of nanocarriers and degradable compounds must also be
considered for safety. Site-targeted delivery of nanoparticles coated
with curcumin and antibodies could enhance treatment efficiency and
it can also alleviate the toxicity of nanocarriers as well as higher
concentration

Nanoparticles loaded with curcumin are transformed as

chemotherapeutic agents for curing multiple diseases ranging from
inflammatory to cancer and viral diseases. In addition to development
of bioavailability by oral administration, intravenous administration
could benefit more since it can directly reach the site of action earlier.
Development of analogues of curcumin and nanocarrier with receptor-
mediated assistance would be much useful. Though a few studies have
demonstrated biochemical pathways of pharmacological actions of
curcumin, comprehensive understanding of mechanistic actions of
curcumin-loaded nanoparticles at molecular level and their impact and
possible toxic/adverse effects need to be thoroughly studied before its
acceptance as commercial drug.

Kunyit (Curcuma longa) merupakan tanaman yang dapat tumbuh di daerah tropis dan sub tropis, serta
merupakan tanaman asli Asia Tenggara. Di Indonesia, kunyit menyebar secara merata di seluruh
daerah. Kurkumin yang merupakan unsur utama kunyit, merupakan antioksidan yang kuat. Beberapa
penelitian juga menunjukkan bahwa kunyit mampu menghambat pertumbuhan beberapa tipe sel
kanker. Mekanisme anti-kanker kurkumin adalah dengan menghambat proliferasi sel. Penelitian
terdahulu melaporkan bahwa ekstrak Curcuma longa menginduksi apoptosis pada sel HeLa, tetapi
mekanisme kematian sel tersebut belum jelas.

Kurkumin berperan dalam pengontrolan siklus sel dan stimulasi

apoptosis melalui regulasi p16 dan p53, dan
ketiga kurkumin merupakan modulator
autophagy
dan mempunyai efek penghambatan terhadap
angiogenesis tumor dan menghambat metastasis
melalui supresi berbagai
growth factor
termasuk
VEGF, COX-2, MMPs and ICAMs. Meskipun
demikian tidak semua penelitian menunjukkan
kurkumin mampu menginduksi apoptosis pada
sel kanker. Diantaranya adalah penelitian yang
dilakukan oleh Moos
et al.
8
yang menunjukkan
bahwa kurkumin menghambat apoptosis yang
diinduksi oleh p53 (
tumor supression protein
) pada
kultur sel kanker kolon. Kurkumin juga menginhibisi
apoptosis pada kultur sel kanker payudara dengan
konsentrasi 1-10 μM/liter.
9
Berdasarkan hal-hal
tersebut maka penting untuk dilakukan penelitian
lebih lanjut tentang mekanisme molekuler kurkumin
dalam menginduksi apoptosispada sel HeLa yang
merupakan model sel kanker epitelium.
KESIMPULAN
Kurkumin menyebabkan kerusakan sel pada
sebagian besar sel HeLa berupa
shrinkage
yang
merupakan ciri apoptosis.