Super anti cancer fruit - Custard apple

Anti-Cancer Properties

Difficulties with most of the chemotherapeutic drugs emanate from their concurrent eradication of normal healthy cells, including those responsible for immunity (www.pawpaws.net, 2010).  Tumor cells grow and replicate more rapidly than normal cells.  This is because they are better equipped to receive glucose, a good source of energy for fast replication.  Also, cancer cells quickly develop a network of blood vessels (angiogenesis) to ensure an efficient supply of nutrients and oxygen.  This is partly why cancer patients lose weight; the cancer cells rapidly take up nutrients meant for normal cells.  Furthermore, with chemotherapy cancer cells develop resistance to the drugs, rendering chemotherapy useless and futile after a period of remission (www.pawpaws.net, 2010).

Cancer cells smartly find a way of protecting themselves from the damaging effects of drugs. They generate what is called the ABC transporter superfamily, which transports a variety of substrates including amino acids, sugars, inorganic ions, polysaccharides, peptides, and proteins into the cells (Yong-Ju Liang et al., 2009).  In cancer cells, a member of this superfamily, called the multidrug resistant (MDR) protein, is overexpressed and helps to pump drugs out of the cancer cells, making the cancer cells simultaneously resistant to a variety of drugs.  Thus, the cancer cells are protected from the toxic effects of drug combinations (www.pawpaws.net, 2010).

14.1 Discovery of acetogenins

The anti-cancer properties of custard apple appear to be mainly due to a class of compounds called acetogenins which are specific to Annonaceaous species (Alai et al., 1999; McLaughlin, 2008).  Acetogenins are very long chain fatty acids (McLaughlin, 2008).  Throughout the 1990s, a team of researchers lead by Professor Jerry McLaughlin at Purdue University, in West Lafayette, Indiana, and another team at Kaohsiung Medical University, Kaoshiung Taiwan have evaluated the structure and anti-cancer properties of acetogenins.

To date, over 400 acetogenins have been identified (McLaughlin, 2008; Li et al., 2008).  Currently the Annonaceae remain a "hot' family for the discovery of new anti-cancer drugs.  Chinese and Taiwanese universities have successfully synthesized a range of these acetogenins (Li et al., 2008).

14.2 In vitro testing

Acetogenins have been tested in vitro against 60 types of cancer cells, including breast, prostate and colon (Fang-Rong et al. 1999; Alai et al., 1999; Chih et al., 2001; McLaughlin et al., 2005; McLaughlin, 2008).  Leaf and seed extracts of acetoegnins exhibited powerful in vitro cytotoxic and anti-cancer properties, up to 200-300 times more powerful than some currently used drugs such as Taxol (McLaughlin, 2008).

Thus far, specific acetogenins have been reported to be selectively toxic in vitro to the following types of tumour cells (Fang-Rong et al. 1999; Chih et al., 2001; McLaughlin et al., 2005; McLaughlin, 2008).

• lung carcinoma cell lines
• human breast solid tumour lines
• prostate adenocarcinoma
• pancreatic carcinoma cell lines
• colon adenocarcinoma cell lines
• liver cancer cell lines
• human lymphoma cell lines
• leukaemia
• multi-drug resistant human breast adenocarcinoma

14.3 In vivo (living organism) testing

McLaughlin et al. (2006) showed that the acetogenin, bullatacin, was active in reducing the development of leukaemia in mice.  Compared with Taxol (paclitaxel) a standard anti-cancer drug, bullatacin was 300 times as potent as taxol in this in vivo test system.  Cuendet et al. (2008) showed that Asimina triloba extract containing acetogenins increased mammary tumour latency from 55 to 66 days in Sprague-dawley rats.

14.4 Human clinical trials

Limited human clinical testing trials are being conducted on the closely related Annonaceous species Asimina triloba (North American pawpaw) at the Cancer Screening and Treatment Centre in Nevada, USA with apparent promising results (visit www.pawpaw.research.com site for details).  A standardized pawpaw extract called Pawpaw Cell-Reg, containing mixtures of Annonaceous acetogenins and capsules of dried sugar apple pulp are being sold commercially.

14.5 Mode of action

Annonaceous acetogenins may be good chemotherapeutic agents for cancer (Ahammadsahib et al., 1993; Oberlies et al., 1995, 1997; Chih et al., 2001).  These compounds inhibit mitochondrial and cytoplasmic production of adenosine triphosphate (ATP), which is the major source of energy for the cells and also a precursor of the nucleotides needed to produce DNA and RNA. Annonaceous acetogenins also inhibit the enzymes of complex I in the electron transport system in mitochondria (Oberlies et al., 1999, McLaughlin, 2008; McLaughlin et al., 2010).  They also inhibit the NADH oxidases found in the plasma membranes of tumor cells (McLaughlin, 2008).  Their net effect is depletion of ATP levels.

Tumor cells, being typically metabolically more active, are more susceptible than normal cells to the effects of the acetogenins (McLaughlin, 2008).  For example, breast cancer cells can take glucose seventeen times faster than normal cells.  Angiogenesis requires ATP and angiostatin blocks angiogenesis by inhibiting ATP synthase (McLaughlin, 2008).  Thus, ATP depletion helps to block the growth of new vessels to nourish tumors

Annonaceous acetogenins also thwart multi drug resistant (MDR) tumor cells (Oberlies et al. 1997).  The protein pumps (glycoproteins), which extrude the drugs from the tumor cells are energized by ATP.  Thus, by depleting ATP, the glycoproptein pumps become dysfunctional.

Acetogenins can also induce apoptosis (programmed cell death) of certain cancer cell lines (Yong-Ju Liang et al., 2009) (Figure 9).  Apoptosis is an important mode of action for many antitumor agents.  It is a protective measure against malignant transformation; in fact effective tumor therapy may involve the induction of apoptosis.