INTRODUCTION:

Currently used chemotherapeutic agents are found to be harmful to the normal cells because of which phytochemicals with anticancer activity obtained from natura sources which are found to be safe are preferred. There is an increasing demand for an alternative, noninvasive treatments and preventative measures preferably naturally occurring phytopharmaceuticals. Phytochemicals are obtained from plant origin and may be used in the dried or fresh form or as extracted material. They possess numerous properties like antioxidant, anti-inflammatory, and immunomodulatory properties, and emerged, out as best chemotherapeutic agents.^1,2,3

Andrographolide: An Active Therapeutic Agent:

The Andrographolide is isolated using the leaves and roots of Andrographis paniculata (Burm .f.) Wall ex Nees, a labdane diterpenoid derivative.⁴ The highest concentration of Andrographolide is found from the one extracted using the leaves of Andrographis paniculata.

The quantity of Andrographolide obtained is the highest during the vegetative stage that is before the flowering stage.⁵ Chemically Andrographolide is (3-[2-[decahydro-6-hydroxy-5-(hydroxymethyl)-5, 8-adimethyl-2-methylene-1-napthalenyl] ethylidene] dihydro-4-hydroxy-2(3H)-furanone). It showed weaker anti-microbial activity.⁶Because of its bitter taste Andrographis paniculata is commonly known as “King of bitters”⁴. Also known with various names like Kalmegh, Chanxinlian, fah tha lai, Sambiloto in Indonesia and Hempedubumi in languages like Hindi, Chinese, Thai, and Malaysian. The family to which Andrographis paniculata (Burm. f) Nees (synonyms A. Paniculata var. glandulosa Trimen., Justicia paniculata Burm. f), belongs is Acanthaceae. It is seen abundantly in the countries like India, China, Srilanka and Malaysia ^6,7. Since ancient time Kalmegh was used in the treatment of heat and dampness due to its cooling properties. Report also suggested its anti-diabetic and anti-hypertensive properties in the countries like Thailand and Malaysia. It was preferred as a remedy for fever and common cold in the Thai Scandinavian countries.⁸ The plant extract possesses multiple applications such as Liver Stimulant (Yakriduttejaka), carminative (Deepana), Pittasaraka, antileprotic (Kusthaghna), antipyretic (Jwaraghana) clearing toxins from blood (Rakta shodhaka), Laxative (Rechana), inflammation reducer (Shothahara), swedajanana, anthelmintic (Krimighna) and it also act as a preventive major for malaria (vishmajwara-pratibandhaka).⁹

It was also found to be effective incase of snake bite. Research carried out proved that the plant has potential benefit and is also found to be useful as an anti-inflammatory, anticancer, antimicrobial, antihyperglycemic and immunoregulatory agent.⁴Andrographis paniculata can also reduce the elevated body temperature and able to expel toxins from the body.⁹ 300 to 1800 mg/day dose was used for human trials.¹⁰The rate of absorption and metabolism was found to be extensive in the rats and human. It was also found that ninety percent of it was eliminated within 48 hrs.¹¹Rasa-Tikta, Ruksha, Vipaka-Katu, Guna-Laghu, Veerya-Ushna, Doshaghnata-Kaphapittashamaka, Viapaka-Katu are the inherent characteristics of Andrographis paniculata hence it is used to cure variety of disorders. It is available in the form of Bhunimbadyashtadashanga kwatha, Devadarvyadi kwatha churna, Tiktaka ghrita, Argvadhadi kwatha churna, Pathyadi kwatha churna, Bhunimbadya ghrita, Nimbadi kwatha churna and Bhunimbadi kwatha, in the Ayurvedic system. It is available in the Juice (5-10ml), Decoction (20-40ml), liquid extract (0.5-1ml) and powder (1-3g) form.¹¹ Various Physicochemical properties of Andrographolide are summarised in the Table 1^6,8,12

Table 1: Physicochemical properties of Andrographolide

Drug	Andrographolide
Chemical Structure
Constituents obtained from plant Andrographis. Paniculata	neoandrographolide, isoandrographolide and 14-deoxy-11, 12-didehydroandrographolide, flavonoids, xanthone, quinic acid and its derivative, sitosterol, and polysaccharide
Melting Range	228-230⁰C.
Extraction Technique	Soxhlet Method and supercritical carbondioxide extraction

Research on Andrographolide by Al Batran et.al. on administering 500mg/kg dose shows no sign of toxicity symptoms in the vital organs of rats.¹³

Varma A et.al. observed no inflammatory responses and effect on haematological parameters were observed on the liver, kidney and heart of mice after administering an oral dose of 2000milligram/kilogram and even no increase in the weight of body and weight of organs were observed.⁹

Wong S.K et.al. observed that on administering 100-750 milligram of Andrographolide through IV route acute toxicity was observed in the vital organs like kidney at an average age of 31.3 years.Andrographolide on oral administration, was found to absorb into the blood of which 55% was forming a complex with the blood protein and distributed among the various organs like liver, kidney, spleen, heart and lung.0.1mg/kg dose in rodents provided protection against the brain injury caused by bloodlessness.¹⁰

Naik PP et.al. found that andrographolide exhibited antiplatelet effect by inhibiting formation of thromboxane A2 (TxA2) and hydroxyl radicals (OH−) in washed as well as activated platelets.¹⁴

Andrographolide even was found to reduce cardiac fibrosis and improved the cardiac functioning.¹⁰

Andrographolide as a potent antineoplastic agent in cancer chemotherapy:

Diterpenoids obtained from Andrographis. paniculata were found to be effective against various types of cancer.^9,15

Cytotoxic activity was produced against human cancer cell lines like PC-3 (prostrate), HepG2 (hepatoma), Colon 205 (Colonic) and Jurkat (lymphocytic) cells by the ethanolic extract of Andrographis paniculata. A comparative study was carried out on human leukaemia HL-60 cells using andrographolide, isoandrographolide and 16 ent-labdane diterpenoids and the former two exhibited higher antiproliferative activity with the half- maximal inhibitory concentration value of 9.33 and 6.30 μM.¹⁶ Mechanism of Action of Andrographolide for exhibiting cytotoxic activity includes inhibiting the multiplication and inducing programmed cell death in case of cancerous cells.^15,17

Positive Regulation of Cell Cycle:

Using Human Acute HL-60 cells, Andrographolide showed an increase of 27% in case of G0/G1 phase and reduction of S and G2/M phase was observed. The 12 μg/ml concentration of Andrographolide was found to be effective in producing the desired effect after carrying out the study for 36 hrs. The inhibitory effect was observed in case of down-regulation of progression through cell cycle and even it modulated positive regulation of cell cycle arrest related proteins. The expression of cyclin A, cyclin D, CDK4 and CDK2 mandatory for G1 to S transition was decreased by induction at G0/G1 phase using the cell cycle inhibitory proteins (p16,p21, p27).^16,17,18A research conducted on Andrographolide by Shi et. al. caused inhibition of human colorectal carcinoma lovo cells in the concentration of 10-30μM.¹⁸

Induction of Apoptosis:

The extrinsic death receptor pathway was activated by Andrographolide. The apoptotic cell death caused among several human cancer types by caspase-3 and caspase-8 pathway. Activation of caspase 3/7 and amplification of signal through mitochondria is caused because of the activation of caspase-8. Andrographolide enhances the expression of TRAIL which ultimately induces apoptosis. The resensitization of the resistance cancer cell to TRAIL and also enhancement of expression is caused by increasing response towards death receptor (DR-4). The rate of apoptosis in multidrug resistant cancer cell increases when Andrographolide is combined with 5-florouracil, Adriamycin and cisplatin.^18,19,20

Andrographolide inhibited NF-κB, proliferation and apoptosis and regulate LKB1/AMPK/mTOR signaling pathway. Reduction in taking up of p65 and IκBα along with blocking of NF-κB activation using diterpenoid was depicted using in vivo model. The suppression of the activity of cyclin D1, survivin and NF-κB target genes EGFR was also demonstrated.^15,17,20

The inhibition of the proliferating cancer cells is caused by the fractionated extract of Andrographis paniculata into the aqueous, methane and ether. The aqueous extract obtained was found to be the non-active. The induction of IL-2 formation and increase in multiplication of borderline blood lymphocytes exerted the anti-cancer and immunomodulatory activity.^20,21

It was found that the use of anti-toxic concentration of Andrographolide, the TRAIL-induced apoptosis was caused by increasing the sensitivity of PCA. The regulatory mechanism which caused increase in DR4 regulation was the mechanism responsible for the same. The reactive oxygen species (ROS) making in cells was triggered due to increase in the expression of p53. The reduction of TRAIL and andrographolide-induced cell death in PCA cells was because of holding back of ROS production, DR4 expression and p53 expression⁶. The detailed mechanism is explained in Figure 1

Figure 1: Regulation of the intrinsic and extrinsic apoptosis pathways by Andrographolide and its derivatives.

Andrographolide- an immunoprotective agent:

The skin cancer is normally caused by the inflammation and oxidative stress.^22,23

Georgakilas et.al. in the year 2012 reported that the oxidative stress injury which is responsible for impairing the function of DNA and carcinogenesis because of excessive generation of ROS resulting in depletion of catalase (CAT) and superoxide dismutase (SOD) an antioxidant enzyme of skin.²³

Zhong Q.Y et.al. investigated the pathology of skin to investigate about carcinogenesis and used the chemically synthesized andrographolide sodium sulphate and found that the UV-induced ROS overproduction, enhancement of activity of SOD and CAT was reduced.²⁴

Candido et.al. in the year 2013 found that the proliferation of mutant cell is because of the inflammatory microenvironment. The monitoring of the inflammatory cells is carried out by neutrophils and monocytes which are activated by cells called CD11b.²⁵

Ghahartars et.al. found out that the development of skin carcinoma is because of IL-6 and TNF-α. The use of the ASB showed a reduction in UV-induced inflammatory cell infiltration, protein amount of the IL-6 and TNF- α and CD11b+ cells which ultimately lead to the prevention of skin carcinogenesis.²⁶

From the research carried out by Kim et al., in the year 2014 it was found that the enhancement of activity of NF-κB could cause hyperplasia along with hypertrophy of mouse epidermis. The results proved the inhibition of NF- κB and Nrf2 activation caused by ASB on long term exposure to UV radiation.²⁷

Research by Mao et.al. proved the NF-κB activation which was caused by p62 by TRAF6 binding domain (TB) and even promoted the expressions of inflammatory genes, that leads to producing signals before inflammation and carcinoma.²⁸

Wang et.al. found that Nrf2 and phosphorylated p62 battles for binding with Keap1 by the activation of Nrf2²⁹

The self consumption of cells, degradation of lysosyme of p62 and aggregation of entire protein is promoted by p62 binding with LC3 in case of cells with normal autophagy ability. There is increased in the expression and accumulation of p62 by reduction in p62 degradation in case of autophagy deficient cells. The results obtained showed no outstanding dissimilarity in p62 and mRNA amount among the batch but increase in p62 and LC3-II/I amount in case of skin carcinoma. Long- term UV exposure showed an impact on skin carcinoma by impaired autophagy. The autophagy flux was restored and expression of LC3-II/I and p62 was decreased by the topical pretreatment. The results indicated that ASB offered protection against ultraviolet radiation induced skin carcinoma by reimposing cell eating.³⁰ The detailed mechanism is shown in the Figure 2

Figure 2: Mechanism of UV induced skin carcinoma and its treatment using ASB

Analogues of Andrographolide:

DRF3188 a newer man-made cognate of andrographolide produced anti-neoplastic activity through similar mechanism like andrographolide but at lower doses. The anti-cancer activities expressed by andrographolide and its cognate is because of D12(13) double bond or epoxy moiety and intact α-alkylidene γ-butyrolactone component of andrographolide which is a novel cytotoxic agent. After screening 60 human tumour cell lines for testing semi-synthetic derivative of andrographolide it was found that the isopropylideneandrographolide showed selective activity against blood and rectal carcinoma cells but 14-acetylandrographolide leukaemia, ovarian and renal carcinoma cells. It was even found that the benzylidene derivatives of andrographolide is more effective than andrographolide in fighting against cancer. Andrographolide along with 5-Florouracil produces Combination of andrographolide with 5-Fluorouracil induces programmed cell death. Andrographolide when combined with doxorubicin enhances the sensitivity of cancer by suppressing JAK-STAT3.³⁰

Drug Interactions of Andrographolide:

Research by Chao-Feng Chien et al proved the group under testing which is pretreated with andrographolide and Andrographis. paniculata showed significant increase in the clearance and reduction in the area under the plot of plasma concentration of a drug versus time on administering low dose of theophylline (1mg/kg). The Pharmacological half-life and mean dwell time was found to lower by 14% and 17% respectively on theophylline (5mg/kg). Due to inherent property of Andrographis Paniculata of prevention in blood clot and inhibition in platelet aggregation was observed on administration of andrographolide with the anticoagulants which increased the risk of bruising and bleeding. Andrographis. Paniculata showed immunostimulatory effect because of which reduction in the activity of immune-suppressant was observed.³¹Research by Pannosian et al proved that on orally administering extract of Andrographis. paniculata of 200,600 and 2000mg/kg dose it didn’t show effect on the increased levels of progesterone in rats during the initial days of pregnancy.³³The comparative study carried out by Hovhannisyan et al. in 2005 using the herbal products Kan Jang and Warfarin showed no impact on the PK-PD profile of Warfarin.³²

Contraindications:

As per the in vivo studies carried in mice and rabbits abortifacient activity was proved of Andrographis Paniculata. But on administration of 2g/kg of body weight of extract of the aerial parts intragastrically during the first 9 days of gestation no abortifacient activity was observed . During pregnancy and lactation higher dose of Andrographis Paniculata should be avoided.^8,11

Dosage forms containing Andrographolide along with the methods of estimation:

Andrographolide which is a bitter tasting drug has poor aqueous solubility. As the solubility is poor the absorption is also poor so ultimately the drug has low oral bioavailability. In the earlier days the Andrographis paniculata plant extracted tablets were prepared as per Chinese pharmacopeia whereas the bioactive component of andrographolide was developed into the pill. Andrographolide was chemically modified with the addition of sodium bisulfate and injection dosage form was formulated. The various dosage forms prepared using andrographolide includes the liposomes, niosomes, microemulsions, solid lipid nanoparticles, polymer entrapment, complexation with a cyclodextrin, and microspheres.³³

A. Suneetha et.al. developed UV Spectrophotometric method for estimating the content of Andrographolide using the plant extract. The formation of coloured complex using picric acid was used to confirm the compound. It showed linearity in the beer’s range of 10 - 100µg/mL.³⁴

Ghumare. P et.al. determined the Andrographolide present in Arjuna extract and Arjuna Tablet using HPTLC. On applying alcoholic solution of extract on the pre-coated TLC plates. The solvent front used was Toluene: Methanol (4:3) v/v. Samples were analysed by densitometric technique at 254nm. Test results were found to comply with the I.P. specifications.³⁵

Bhope SG et.al. quantified andrographolide using HPTLC method in the kalmegh extract as well as in the formulation. The mobile phase used was the toluene: ethyl acetate: formic acid : methanol (50:30:05:2.5 v/v/v/v). Evaluation was carried out densitometrically. The RF value was found to be 0.34±0.03 in case of extract as well as in the dosage form.³⁶

Jadhao. M et.al. used HPTLC technique to standardised and validate herbal powder and polyherbal formulation of Andrographis paniculata. The amount of Andrographolide present was estimated densitometrically. Benzene: ethyl acetate (5:5) was used as the mobile phase. Samples were analysed densitometrically at 220nm. The linearity was observed in the results.³⁷

Sari.R et.al. used andrographolide loaded chitosan-alginate microparticles to obtain the effect on physical characteristics by changing the concentration of alginate. Formulation was analysed using various analytical techniques.The results obtained showed change in the crystallinity of andrographolide after encapsulating in the microparticles. The increase in the concentration of alginate showed a roughness in the surface morphology.³⁸

Saini. V et.al. used thin film hydration technique to prepare phytosomes using the extract of Andrographis paniculate in methanol. The prepared formulation showed a variation in the phospholipid and Andrographis paniculata extract ratio. The prepared formulations were analysed for various physicochemical characteristics and the results obtained were found to be within the pharmacopoeial limit³⁹

Afokoghene. A.J et.al. aqueous and ethanolic extract based cream was formulated using Andrographis. paniculata after antimicrobial screening. The formulated creams were evaluated for various characteristics. The pure ethanolic extract showed sensitivity towards microorganism while aqueous extract was found to be resistant. The MIC of the formulation was found to be 150mg/mL. The resuts of the study proved that the formulated cream formulation was found to be stable.⁴⁰

Shakila R et.al. developed fingerprints using different extracts of Andrographis echiodes Nees andAndrographis paniculata Nees using TLC and HPTLC. Organic solvents were used to prepare the extract. The TLC photo documentation, post derivatization and HPTLC technique revealed the difference in the origin of the compound ⁴¹

Mamillapalli. V et.al. formulated polyherbal vanishing cream and face wash. The formulations were evaluated for various physical parameters along with the antimicrobial activity. All the formulations showed good amount of flavonoids which is used to protect the skin against damage. The formulations showed better anti-microbial activity in comparison to the marketed formulation .⁴²

Types of Skin Carcinoma:

The primary defence mechanism of the n body is the skin which protects the internal environment from the external factors.⁴³In addition skin regulates body temperature and also acts as an excretory organ.² Skin carcinoma is the most common type of malignancy. According to the research carried out in USA it was estimated that almost 1 out of 5 Americans develop skin carcinoma. Based upon clinical behaviour carcinoma may be classified as Non-melanomatous skin carcinoma and Malignant melanoma. Further on the basis of cells affected non-melanomatous skin carcinoma is classified as basal cell carcinoma and squamous cell carcinoma..^43,5

Figure 3: Classification of Skin Carcinoma^{43,44,5,45,46,47,48,49}

CONCLUSION:

Andrographolide a labdane diterpenoid isolated from the leaves and roots of Andrographis. Paniculata. Andrographis Paniculata (Burm .f.) Wall ex Nees called as “King of bitters”. The previous research carried out proved that it even possesses anti-inflammatory, anticancer, antimicrobial, antihyperglycemic and immunoregulatory properties. Diterpenoids were found to be effective against various types of carcinoma which includes the glioblastoma, colon, head neck, breast, skin and prostate carcinoma.^.The cytotoxic property of Andrographolide is because of its ability to induce apoptosis and inhibit propogation and prevail apoptosis in the carcinoma cells. Andrographolide, chemically modified with the addition of sodium bisulfate and injection dosage form was formulated. The various dosage forms prepared using andrographolide includes liposomes, niosomes, microemulsions, solid lipid nanoparticles, polymer entrapment, complexation with a cyclodextrin, and microspheres.

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Received on 13.07.2023 Modified on 20.01.2024

Research J. Pharm. and Tech 2024; 17(7):3514-3520.

DOI: 10.52711/0974-360X.2024.00549