Royleanolic acid

In China, the plant is used to counteract skin putrefaction, heal boils, treat catarrh, dispel humors, and stop dysentry. In Korea, the plant is used to treat anuria and expel intestinal worms. In Cambodia, Laos, and Vietnam, the plant is used to treat colic, cholera, and dysentery.

Fig. 97. Salvia japonica Thunb.

The plant is known to elaborate a diterpene quinone known as royleanonic acid, which is an antioxidant (50). What is the activity of royleanonic acid against topoisomerase? Salvia japonica Thunb., or shu wei ts'ao, wu ts'ao, shui-ch'ing, shu wei cao (Chinese), is an annual herb that grows in marshes in China and Taiwan. The stems are erect, up to 60 cm, villous, and quadrangular. The leaves are pinnate. The petiole is 7-10 cm; the leaf blade is 6-13.5 X 5-9.5 cm; the upper stem leaves are one-pinnate. The flowers are packed in bunches on terminal racemes or panicles. The corolla is reddish to purple and 1.2 cm long. The nutlets are brown and minute (Fig. 97). The plant is used for black dye in China. The flowers and leaves are used to treat fluxes, colorless and red discharges, goiter and scrofula, ague, and dropsy. The rhizome is used for anemia, uterine hemorrhages, irregular menses, abdominal pains, inflammation, and as an antiseptic. Salvia miltiorrhiza Bunge, or red sage, tan shen, or dan shen (Chinese), is a common perennial herb of China, especially in hillsides, streamsides, and forests from 100 to 1300 m in Shensi, Shansi, Shantung, in the Peking mountains, and Japan. The leaves are hirsute. The root is red outside and purplish inside when fresh. The stems are erect, up to 80 cm tall, hirsute, and many-branched. Leaves are simple to impari-pinnate and densely hirsute. The blade is circular to broadly lanceolate and crenate.

Fig. 98. Salvia miltiorrhiza Bunge.

The influorescences are terminal or axillary. The flowers are tubular, bilabiate, purple-blue, violet, or white, and 2-2.7 cm and pilose. The nutlets are ellipsoid and 3.2 X 1.5 mm (Fig. 98).

The drug consists of dried short pieces of roots, which are brick red-colored, with a sweet taste resembling to liquorice. This herb is regarded as one of the five astral remedies by Chinese practitioners who recommend it for the cardiovascular system and blood-related ailments, such as hemorrhages and menstruation, and to promote healing of wounds.

Extract of the plant inhibited the proliferation of HepG2 cells cultured in vitro and caused apoptotosis (51). Chor et al. investigated the effects of a number of Chinese medicinal herbs on cellular proliferation and apoptosis of a rat hepatic stellate cell line, HSC-T6, and found that Salvia miltiorrhiza has antiproliferative and pro-apoptotic activities (52). The active principle involved here might be a diterpene of the tanshi-none type because tanshinone IIA, from Salvia miltiorrhiza Bunge, is cytotoxic against various human carcinoma cell lines cultured in vitro accompanied by an increase in intracellular calcium. This triggers the release of cytochrome c, thus causing a loss of the mitochondrial membrane potential, which results in the subsequent activation of caspases, hence apoptosis (53).

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Fig. 99. Examples of natural products that interfere with apoptosis.

Fig. 99. Examples of natural products that interfere with apoptosis.

Tanshinone II

Tanshinones isolated from the dried root of Salvia miltiorrhiza Bunge abrogated the survival of P388 lymphocytic leukemia cells cultured in vitro. Tanshinone I and tanshinone IIA showed 86.76 and 56.05% cell inhibition, respectively, at a dose of 25 (ig/mL) (54). Dihydrotanshinone I and cryptotanshinone were relatively cytotoxic (55). Dihydrotan-shinone I induces cell growth arrest during the S phase and, subsequently, apoptosis.

Fig. 100. (Continuation): Examples of natural products that interfere with apoptosis.


Fig. 100. (Continuation): Examples of natural products that interfere with apoptosis.

The evidence that emerged from the pharmacological study of Salvia miltiorrhiza Bunge lends strong support to the fact that tanshinone and congeners induce apoptosis. However, if the apoptotic potential of tanshinones is established, much less work has been done with the anti-topoisomerase activity of this planar compound. Further work on this topic should be encouraged, and one can reasonably expect interesting results not only in terms of antineoplastic agents but also in regard to a better understanding of the actual relationship between topoisomerase inhibition and apoptosis. What is the relationship between topoisomerase inhibitors and apoptosis induction?

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